DD201888A5 - PROCESS FOR THE PREPARATION OF 1-CARBOXY-AZAALKANOYLINDOLIN-2-CARBONSAEURES - Google Patents

Abstract

The invention relates to a process for the preparation of 1-carboxy-azaalkanoylindolin-2-carboxylic acids for use as medicaments, for example for the treatment of heart diseases such as heart failure. The aim of the invention is the provision of hypotensive, antihypertensive and bradycardic compounds. According to the invention, compounds of the formula I are prepared in which, for example: Ph is unsubstituted 1,2-phenylene or an optionally substituted 1,2-phenylene; R 1 is lower-valent, lower-alkyl or lower-alkyl; R is lower-2 lower-alkyl or HPh-lower-alkyl; and each of the symbols R deep 3, R deep 4 and R deep 5 is hydrogen or lower alkyl; their amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carboxy-lower alkoxy) -lower alkyl esters, and their salts. You can e.g. by hydrolysis of a compound of formula II wherein at least one of the symbols V and W is cyano and the other represents the said free, amidated or esterified carboxy group.

Description

Berlin, the 4.5.1932

AP C 07 D / 234 536/1 60 058/12

Process for the preparation of 1-carboxy-azaalkanoylindoline-2-carboxylic acids

Field of application of the invention

The invention relates to a process for the preparation of novel 1-carboxyzazaalkanoylindoline-2-carboxylic acids having valuable pharmacological properties, especially hypotensive properties,

The compounds according to the invention are used as medicaments, for example for the treatment of heart disease such as heart failure and / or other conditions dia accompanied by edema or ascites, for _a B ₄₁ liver cirrhosis,

Characteristic of the known technical solutions

1-Alkanoylindoline-2-carboxylic acids and their 5,6-dihydroxy derivatives, namely the N-acylated cyclodopa derivatives are described in Nippon Kagaku Zasshi 87, 760 (1966), in US Pat. No. 3,796,723 and in HeIv, Chim _e Acta 53, 1701 (1970). z "Β * as examples of the synthesis of O- and / or N-acyl compounds, also described * - (carboxy-azaalkanoyl or azaaralkanoyl) · (azetidin». pyrrolidine or piperidine) -2-carboxylic acids and their functional derivatives are, for , B "from the European patent 0012 401 known as compounds with antihypertensive effect *

ZJeI _{1 of} the invention

The aim of the invention is the provision of new agents with improved antihypertensive effect »

4.5,1982

AP C 07 D / 234 586/1 - la - 60 058/12

Explanation of WeSe ₁ IiS ₁ of Erfindunp

The invention has for its object to find new compounds with the desired properties and processes for their preparation,

It has now surprisingly been found that superior antihypertensive agents are obtained either by the introduction of a carboxy group and an aza moiety into the aforementioned indolines, or by extension of the above pyrrolidines to indoline ring systems *

The present invention therefore relates to the novel 1-carboxy (azaalkanoyl or azaaralkanoyl) -indoline-2-carboxylic acids of the general formula 1

_Ph

C-R.,

N COOH

CO-CH-NH-CH-COOH I I

_ 2 -

wherein Ph represents unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different substituents of the group lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogen or trifluoromethyl, R represents hydrogen, lower alkyl or amino-lower alkyl, R "is lower alkyl or HPh lower alkyl and each of the symbols R", R, and R_ is hydrogen or lower alkyl; their amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or lower carbonyl) lower alkyl esters, and their salts, in particular their therapeutically acceptable salts, and processes for their preparation, pharmaceutical preparations containing these compounds , as well as their therapeutic use.

The 1,2-phenylene group Ph and / or the phenyl group HPh are preferably unsubstituted or monosubstituted. Their substituents can be illustrated by the following groups: lower alkyl, e.g. Methyl, ethyl, n- or iso-propyl or -butyl; Lower alkoxy, e.g. Methoxy, ethoxy, n- or isopropoxy or butoxy; Lower alkylenedioxy, e.g., methylenedioxy, 1,1- or 1,2-ethylenedioxy; hydroxy; Halogen, e.g. Fluorine, chlorine or bromine; or trifluoromethyl.

A lower alkyl group R and / or R is preferably methyl, ethyl, n- or iso-propyl or -butyl. The amino-lower alkyl group R is preferably t * 3 ~ amino (ethyl, propyl, butyl or pentyl); and the . Aryl-lower alkyl group is also preferably HPh-methyl or O) -HPh- (ethyl or propyl).

Each of R ", R and R is preferably hydrogen, but also lower alkyl, preferably methyl, or another previously mentioned lower alkyl group.

The term "lower" defines in the above or below mentioned organic radicals or compounds those having at most 7,

preferably 4, in particular 1 or 2 carbon atoms.

The said functional derivatives in which either one or both carboxy groups are esterified or amidated are preferably mono- or bis-lower alkyl esters, e.g. Methyl, ethyl, n- or iso-propyl or butyl ester; Mono- or bis-amides, or the corresponding N-alkylated amides, e.g. Mono or dimethylamide. The said substituted lower alkyl esters are preferably half esters with a free indoline-2-carboxy group, e.g. the U> - (amino, mono- or dimethylamino, carboxy or Carbethoxy) - (ethyl, propyl or butyl) ester.

Salts are preferably therapeutically useful salts, e.g. Metal or ammonium salts of said acids, especially alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium or calcium salts; primarily easily crystallizing ammonium salts, These are derived from ammonia or organic amines, e.g. 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, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. The basic (amino, mono- or di-lower alkylamino) -lower alkyl esters mentioned also form acid addition salts. These are preferably prepared with those acids which give therapeutically useful acid addition salts. Acids which give therapeutically useful acid addition salts are e.g. inorganic acids such as hydrohalic acids, e.g. Hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid; or preferably organic acids, such as aliphatic or aromatic carboxylic or sulphonic acids, e.g. formic,

Acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, citric, maleic, fumaric, hydroxymalein, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicyl, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sufolanilic or cyclohexylsulfamic acid; or the ascorbic acid.

The compounds of the invention show valuable pharmacological properties, primarily hypotensive, anthiapertensive and bradikardische effects, which they cause inter alia due to their inhibitory effect on the enzyme which converts the angiotensin. These pharmacological properties can be detected by testing in vivo or in vitro, preferably on mammals, such as rats, cats, dogs or their isolated organs. The animals may be either normotensive or hypertensive, e.g. genetically hypertensive rats, or renal hypertensive rats or dogs, and dogs that have been deprived of sodium. The compounds mentioned may be administered enterally or parenterally, preferably orally or intravenously, e.g. by gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used may range from about 0.01 to 50 mg / kg / day, preferably about 0.1 to 25 mg / kg / day, more preferably about 1 to 10 mg / kg / day.

The in vivo hypotensive effect is achieved, either directly with a catheter, e.g. introduced into the femoral artery of a dog, or indirectly registered by sphygmomanometry on the rat's tail, and a transmission instrument. Blood pressure is determined before and after administration of the active substance in mmHg. Thus, e.g. the representative compounds of this invention illustrated in the Examples in hypertensive rats or dogs

even when administered in low oral doses of 10 mg / kg / day or less, very effective.

The novel compounds also show an inhibitory effect on the blood pressure of normotensive rats on angiotensin I. Under normal conditions, the enzyme renin causes a specific hydrolysis of the circulating renin substrate protein. This hydrolysis produces angiotensin I, which is further hydrolyzed into the - strongly vasoconstricting angiotensin II by the action of said enzyme which converts the angiotensin. Inhibition of said enzyme prevents the formation of angiotensin II from I. This inhibition therefore attenuates any response of blood pressure following an angiotein I attack.

The corresponding in vivo test is performed on male normotensive rats anesthetized with 100-120 mg / kg intraperitoneally administered sodium salt of the ethyl- (1-methylpropyl) -malonylthiourea. A femoral artery and a calf vein are each provided with a hollow needle for the direct measurement of the blood pressure and for the intravenous administration of the angiotensin I and the compounds according to the invention. After stabilization of the basal blood pressure, the pressure change is determined after three irritations at 5-minute intervals with 0.33 μg / kg angiotensin I i.V. Pressure changes are also determined 5, 10, 15, 30 and 60 minutes after entx cetaneous intravenous or peroral administration (with gavage) of the compounds to be tested. The latter pressure changes are compared with the initial values. Any noted decrease in blood pressure response is an indication of the inhibition of the enzyme converting angiotensin. This decrease can be up to 80%, after doses of 10 mg / kg i.v. or 50 mg / kg p.o., and last up to 60 minutes.

The in vitro inhibition of the enzyme which converts the angiotensin may be analogous to Biochim in the compounds of this invention. Biophys. Acta 293, 451 (1973). According to this method, said compounds are dissolved in about 1 mmol concentrations in phosphate buffer, which is cooled from the outside with ice. To these solutions are added first different amounts of ul of 1 mM histidine-leucine in phosphate buffer and then 100 μl of 5 mM polar hippuryl-histidyl-leucine in phosphate buffer and 50 μl of the angiotensin converting enzyme. This enzyme is freshly prepared from lungs of adult male rabbits in Tris buffer containing potassium and magnesium chloride as well as cane sugar. The said solutions are incubated for 30 minutes at 37 ° and the further reaction is stopped by adding 0.75 ml of a 0.6-normal aqueous sodium hydroxide solution. Then at room temperature 100 μΐ o-phthalaldehyde and after 10 minutes, add 100 yl of 6 N hydrochloric acid thereto. The samples are compared in a spectrophotometer hot with water and their optical density is determined. These values are adjusted by a conversion factor of a standard curve to give the amount of histidyl-leucine in nanomoles formed during said 30 minute incubation. The results are plotted against the drug concentrations as a graph to determine the IC value. This value means that active ingredient concentration which gives half the activity of a control sample containing no active ingredient. The said representative compounds of the present invention are also very effective in this in vitro assay system, up to the IC value of 39 nM and below.

Accordingly, the compounds of the invention are valuable antihypertensive agents, particularly for the reduction of high blood pressure (without regard to aetiology) and / or cardiac disorders such as heart failure, and / or other conditions associated with edema or ascites, e.g. Liver cirrhosis. You can

also be used as intermediates for the preparation of other valuable products, in particular pharniakologisch effective preparations.

Preferred compounds are those of the formula I in which Ph is unsubstituted 1,2-phenylene or is 1,2-substituted by one or two, identical or different substituents of the group lower alkyl, lower alkoxy, hydroxy and halogen, or by an alkylenedioxy or trifluoromethyl group. Phenylene; R represents hydrogen, lower alkyl or LU-amino-lower alkyl, R represents lower alkyl or W-lower alkyl, and each of R ", R and R represents hydrogen or lower alkyl, their amides, mono- or di-lower alkylamides, lower alkyl esters , (Amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy) -lower alkyl esters and salts, in particular therapeutically usable alkali metal, alkaline earth metal, ammonium salts or acid addition salts.

Preference is further given to compounds of the formula I in which Ph is a 1,2-phenylene monosubstituted by lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogen or trifluoromethyl, R is lower alkyl or -Ü-amino-lower alkyl, R is lower alkyl or U) -HPh-lower alkyl and each of the symbols R, R and R represents hydrogen or methyl, their amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy) -lower alkyl esters and salts, in particular therapeutically useful alkali metal, alkaline earth metal, ammonium or acid addition salts.

Particularly noteworthy are compounds of general formula II

CH NHCH

C EL -R ¹ \ _Ρμ ·) -R "

m 2m 2 η

in particular their indoline-2S-chiral epimers, in which R is hydrogen, alkyl or alkoxy having at most 4 carbon atoms each, hydroxy, halogen or trifluoromethyl, m is an integer from 1 to 4, η is an integer from 1 to 3, R ^{1 is} hydrogen or amino, and R "is hydrogen or R-phenyl; their mono- or bis-inals, the mono- or bis- (lower alkyl or ^ -amino-lower alkyl) esters, and salts, especially therapeutically useful alkali metal , Ammonium or acid addition salts.

Particular preference is given to compounds of the formula II in which R is hydrogen, methyl, methoxy, hydroxyl or chlorine, preferably in the 5-position, m is 1, η is the number 2, R 'is hydrogen and R "is phenyl; Mono- or bis-amides, the mono- or bis (lower alkyl or mono-amino-lower alkyl) esters, and salts, especially therapeutically useful alkali metal, ammonium or acid addition salts.

The compounds of the present invention are prepared by methods known per se, preferably by

1) a Schiff base of the general formula III

(III)

COOH

CO-C (H) (= N) C (H) -COOH 1 PI «IR ₁ R ₂

or their said functional derivatives, wherein one of the symbols

ρ and q is zero and the other is 1, hydrogenated, or 2) a compound of general formula IV

(IV)

COOH X

or their functional derivatives mentioned, with a reactive derivative of a compound of general formula V

Y-CH-COOH (V), I

^R 2

in which X is hydrogen and Y is the moiety HOCO-CHR N-COOR, where R 'is t-butyl or benzyl; or X is CO-CHR-Z and one of the symbols Y and Z is amino and the other is a reactive esterified hydroxy group, condensing, and said COOR group is converted to hydrogen, or

3) a compound of general formula VI

R

• X-Li. V ¹ * * * · t

(VI)

wherein at least one of the symbols V and W is cyano, and the other is the said free, amidated or esterified carboxy group, hydrolyzed or alcoholized, or 4) in a compound of general formula VII

CO-CH-NH-CH-COOH

or in their said functional derivatives, hydrogenating the indole moiety to the indoline moiety and, if desired, converting a compound obtained into another compound of the invention.

The hydrogenation of compounds of formula III is carried out by methods known per se, e.g. either with catalytically activated or nascent hydrogen, such as hydrogen in the presence of platinum, palladium or nickel catalysts, or with electrolytically generated hydrogen, or by the action of metals on acids or alcohols. Also reducing agents, e.g. Simple or complex light metal hydrides, such as boranes, or preferably alkali metal hydrides or cyanoborohydrides, may be used.

Reactive, functional derivatives of compounds of formula V are preferably ester halides, simple or mixed anhydrides, e.g. the lower alkyl half of said acid chlorides, the cyclic anhydride, or mixed acetic or cyanoacetic anhydrides. A reactive esterified hydroxy group Y or Z is preferably halogen, e.g. Chlorine, bromine or iodine, or aromatic sulphonyloxy, e.g. Tosyloxy .. or Brosyloxy. The aforesaid condensation of compounds III and IV proceeds either spontaneously or in the presence of condensate, for example. organic or inorganic bases, such as of said salt-forming amines or alkali metal carbonates or disubstituted carbodiimides. In an obtained compound containing the aza-protecting group COOR, the latter may be prepared according to the methods well known in peptide chemistry, preferably by the previously described catalytic hydrogenation, or by

the hydrolysis described below, be cleaved off. The said starting materials are also known or, if new, they can be prepared according to a condensation analogous to process 2).

The hydrolysis of the nitriles VI to the corresponding acids or amides is carried out in a manner known per se, preferably with inorganic acids, e.g. Hydrochloric or sulfuric acid. The said alcoholysis is carried out analogously, in the presence of said acids and the corresponding unsubstituted or substituted lower alkanols.

Finally, said hydrogenation of indoles VII to the indolines I is also carried out according to the conventional hydrogenations of 1-acylindoles, e.g. with catalytically activated or nascent hydrogen, such as hydrogen in the presence of platinum, palladium, rhodium or nickel catalysts, or with electrolytically generated hydrogen, or by the action of metals on acids or alcohols. Also reducing agents, e.g. Simple or complex light metal hydrides, such as boranes, or preferably alkali metal borohydrides or cyanoborohydrides, may be used. Preferably, the asymmetric hydrogenation to the indoline-2S-carboxylic acids or their derivatives mentioned. In doing so, one uses chiral catalysts, e.g. those prepared from a rhodium salt with (R) -I, 2-bis (diphenylphosphino) -propane or (R) -I, 2-bis (o-anisylphenylphosphino) -ethane and 1,5-cyclooctadiene.

Functional derivatives of carboxylic acids, e.g. those of formulas III, IV, V, VII, R, CHNHCOOH or RCOCOOH are preferably esters, e.g. Lower alkyl esters such as ethyl, t-butyl or aralkyl esters, e.g. Benzyl esters.

Among a reactive derivative of a carboxylic acid in this invention are preferably acid halides, reactive esters,

single or mixed anhydrides or similar compounds known in the art, such as those described for formula V.

The starting materials are known or, if new, may be prepared by methods known per se, e.g. be prepared analogously as described in the examples. New starting materials also form an object of the invention.

Starting materials of formula III are preferably in situ, by condensation of a compound of formula IV, wherein X is the group R COCO, with a compound R CHNH COOH or one of its functional

Z. Jim

Derivatives made. They can also be obtained by condensing a compound IV in which X represents the group R CHNH "CO, with a compound of the formula R COCOOH or one of its functional derivatives. The condensations are carried out in an inert solvent in the absence or in the presence e.g. anhydrous mineral acid or an organic acid (e.g., boron trifluoride, hydrogen chloride or acetic acid), an inorganic salt (e.g., magnesium sulfate) or a molecular sieve.

The intermediates of formula IV, wherein X is the group R COCO. are known or can be obtained by condensing a compound of formula IV or an ester thereof wherein X is hydrogen with an optionally protected (e.g., dithioketal) compound of formula R COCOOH or one of its reactive functional derivatives.

Intermediates of formula IV wherein XR is CHNH CO are prepared by condensing a compound of formula IV or one of its esters wherein X is hydrogen with an optionally N-protected (eg N-benzyloxycarbonyl or t-butyloxycarbonyl derivative) compound of formula R CHNH COOH or one of its reactive ones

functional derivatives, are produced. If necessary, the protected group can subsequently be released again in a manner known per se or as described below. The above or below mentioned condensations with reactive functional derivatives of carboxylic acids proceed spontaneously or in the presence of condensing agents, e.g. inorganic or organic bases, such as potassium carbonate, pyridine or triethylamine. The condensations of carboxylic acids per se may be carried out in the presence of linking agents, e.g. Dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.

Compounds of formula IV in which X represents the group COCHR Z may be prepared by acylating a compound of formula IV in which X is hydrogen with a functional derivative of HOCOCHR ₁ Z wherein Z is a reactive esterified hydroxy group (eg chloro or tosyloxy) or a protected amino group, for example t-butyloxycarbonylamino (t-BOC-amino) or carbobenzyloxyamino (Cbo-amino) means, and conversion into the compound of formula IV, wherein X is the group COCHB. NH "means according to known and described below, for example, hydrolysis under acidic conditions or catalytic hydrogenation, are prepared.

Compounds of the formula V in which Y is HOCO-CHR-N-COOR can preferably be prepared as follows:

a) reacting an ester (e.g., a lower alkyl ester such as t-butyl ester) of a compound of the formula R CHNHCOOH with an ester (e.g., lower alkyl ester such as ethyl ester) of a compound of the formula R "CO-COOH in the presence of a dehydrating agent, e.g. Boron trifluoride.

s:

b) Reduction of the Schiff base obtained by methods known per se, e.g. by hydrogenation in the presence of palladium or nickel catalysts or with a reducing agent, e.g. Sodium cyanoborohydride.

c) protection of the nitrogen in the resulting azadiester with a known reactive functional derivative of R COOH and

d) hydrolysis of an obtained N-protected diester of a compound of formula V wherein Y is HOCO-CHR-N-COOR.

Starting materials of the formula VI in which W is cyano can preferably be prepared starting from a compound of the formula IV in which X is COCHR NH, and a compound of the formula R CHY-CN in which Y is a reactive esterified hydroxy group.

Starting materials of the formula VII can be obtained according to process 2), as described above. In this process, a compound of formula IV is replaced by the corresponding indole compound in which instead of R "and R, a simple bond connecting the carbon atoms carrying R ₀ and R is present.

The obtained compounds of the invention can be converted into other compounds of the invention in a manner known per se. Thus, e.g. obtained amides or esters further hydrolyzed or alcoholized (transesterified). This can be done according to method 3), or with aqueous alkalis, e.g. with alkali metal carbonates or hydroxides. Obtained free acids can be esterified in a conventional manner, with said unsubstituted or substituted lower alkanols or diazoalkanes, or converted into said metal, ammonium or in the acid addition salts.

Thus, e.g. converting a resulting free (amphoteric) compound into a corresponding metal, ammonium or acid addition salt by reaction with an equivalent amount of a corresponding base, basic salt, acid or ion exchanger. The acids mentioned are with alkali metal or

Ammonium hydroxides or carbonates, and said acids, amides or esters with the above-mentioned "inorganic or organic acids treated.A salt obtained can also in the free compound, by treatment with stronger acids or bases, preferably at a pH between about 3 and 5, converted.

Owing to the close relationship between the novel compounds in free form and in the form of their salts, in the preceding and following among free compounds (or intermediates) and salts, it is meaningful and. if appropriate, to understand the corresponding salts or free compounds.

Obtained geometric or optical isomeric mixtures of the above compounds of formulas I to VII can be prepared by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography, are separated into the individual isomers. Racemic products may be incorporated into the optical antipodes, e.g. by separation of their diastereomeric salts, as described in J. Org. Ghem. _43_, 3803 (1978), e.g. by fractional crystallization of d- and ^ - (tartrates, almonds, camphorsulfonates or 1-naphthyl-l-ethyl isocyanates), 'or of d- and ^ - (α-methylbenzylammonium, cinchonidine, cinchonine, quinine, quinidine, ephedrine, Dehydroabietylamine, brucine or strychnine) salts. The preferred starting material of formula III is its 2S optical isomer (epimers).

The above reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert to and dissolve the reagents, catalysts, alkaline or acidic condensation or other agents mentioned above, e.g. the usual, for the protection of the amino group in the peptide synthesis used agents, and / or in an inert atmosphere, with cooling, at room temperature or

at elevated temperatures, preferably at the boiling point of the solvent used, at normal or elevated pressure.

The invention also relates to modifications of the present process, according to which an intermediate obtained at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or in which Starting material is used in the form of a salt or optically pure antipodes.

In the process of the present invention, it is advantageous to use those starting materials which lead to the compounds described above as being particularly valuable, in particular those of the formula II, and which are the following chiral isomers:

ι (S) (S)

CO-CH NH-CH-COOH

C Η _Λ ~ R / ρττ ¹ N r> Il

m 2m 2 η *

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets included

4 * 5.1982

AP C 07 D / 234 586/1 - 17 - 60 058/12

also binder, z * B * magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, z, S * starches, agar, alginic acid or a salt thereof, such as sodium alginate, Enzymes of Binders and / or Effervescent Mixtures, or Adsorbents, Dyes, Flavorings and Sweeteners Injectables are preferably isotonic aqueous solutions or suspensions, and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and / or auxiliary substances, z " S * preservatives", stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, z, B * by means of conventional mixing. Granulating or coating methods prepared and containing from about 0.1 % to about 75 %, more preferably from about 1 % to about 50 %, _{t of} the active ingredient. "Single doses for nipples weighing about 50 to 70 kg can range from about 5 to 100 mg of the active ingredient.

The following examples are given to illustrate the invention. "Temperatures are in degrees centigrade, and parts are by weight." Unless otherwise defined, evaporation of solvents under reduced pressure, e.g., B ₆ , is between about 15 and 100 mm / Hg, performed *

Example 1: A mixture of 1.0 g of 1- (S-alanyl) -indoline-2S-carboxylic acid, 3.8 g of 4-phenyl-2-oxobutanoic acid and 30 ml of water is added to the pH at room temperature with aqueous sodium hydroxide solution. Value 7.5 is set. The mixture is treated with 0.8 g of sodium cyanoborohydride and stirred overnight at room temperature. The mixture is then quenched with 5 mL concentrated hydrochloric acid and filtered through a short column of strong acid ion exchange resin (Dowex 50 W-X4). The column is eluted first with 50% aqueous ethanol (elimination of the starting material) and then with 4% (volume) aqueous ammonia. The latter eluate is evaporated, the residue slurried in 6 ml of water, the pH of which is adjusted to 3 with 1 normal hydrochloric acid and the resulting precipitate collected. The 1- [N- (1-carboxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid of the formula II in which R = R ¹ = H, m = 1, η = 2 and R " = C ₅ H _5, mp 140-146 °, - [α] = -96 ° (c = 0.8 in ethanol).

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 C-cinchonidine are dissolved in 1200 ml of hot ethanol. The white crystalline salt is filtered off and removed, the filtrate is evaporated, 1000 ml of water are added and the solution is adjusted to pH 1 with concentrated hydrochloric acid and after 15 minutes the product is filtered off , washed three times with 250 ml of 2 N hydrochloric acid, twice with 500 ml of water and twice with 100 ml of ethanol to give the 1-acetylindoline-2S-carboxylic acid, which melts at 214-215 °, [α] = -133.3 ° (c = 1.165 in ethanol).

A suspension of 37.5 g of the latter compound in 380 ml of 2 N aqueous hydrochloric acid is first freed from oxygen by passing nitrogen (5 minutes) and then

Boiled under reflux for 2 hours. The reaction mixture is cooled to room temperature, filtered through infusorial earth, the filtrate is evaporated and recrystallized from ether-isopropanol. This gives the indoline-ZS-carboxylic acid hydrochloride, which melts with decomposition at 133 °, [α] = -70.4 ° (c = 1 in ethanol).

A solution of 34 g of the latter compound is saturated without cooling with dry hydrogen chloride. The mixture is stirred for 2 hours at room temperature and the solvent evaporated to the beginning of the crystallization. The concentrate is poured into 400 ml of diethyl ether, cooled to 0 ° for one hour and filtered. The indoline-2S-carboxylic acid ethyl ester hydrochloride, which melts at 179-181 °, gives [α] = -63 ° (c = 1.385 in ethanol).

A mixture of 18.0 g of the latter compound, 18.5 g of N-carbobenzyloxy-S-alanine, 11 ml of triethylamine and 300 ml of methylene chloride is added under stirring at 0 ° with 16.7 g of 1- (3-dimethylamino-propyl) -3-ethyl-carbodiimide hydrochloride added. After one hour, allow the temperature to rise to room temperature and continue stirring overnight. Then the mixture is washed with water, 2 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and evaporated. The 1- (N-carbobenzyloxy-S-alanyl) -indoline-2S-carboxylic acid ethyl ester is obtained.

A mixture of 30.8 g of the latter compound, 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 three times with 100 ml of methylene chloride. The combined extracts are washed with water, dried and concentrated to 50 ml. The concentrate is diluted with 300 ml of diethyl ether, extracted three times with 100 ml of saturated aqueous sodium bicarbonate solution, the combined extracts with

- 20 - WUW 1

acidified concentrated hydrochloric acid and extracted with methylene chloride. The extract is dried and evaporated. The 1- (N-carbobenzyloxy-S-alanyl) -indoline-2S-carboxylic acid melts, which melts at 144-146 °.

A mixture of 15 g of the latter compound, 1.0 g of palladium on carbon catalyst and 150 ml of 90% aqueous ethanol is hydrogenated at room temperature and atmospheric pressure for 2 hours, filtered and evaporated. The 1- (S-alanyl) -indoline-2S-carboxylic acid, which melts at 205-207 °, gives [α] = -141.8 ° (c = 1.1 in water).

Example 2: A mixture of 0.50 g of 1- (S-alanyl) -indoline-2S-carbonic acid, 0.66 g of ethyl 4-phenyl-2-oxobutanoate, 0.43 g of triethylamine, 0.7 g Raney nickel, 2 g of 3A molecular sieve and 20 ml of ethanol are hydrogenated at room temperature and 2.7 atmospheres for 18 hours. The mixture is filtered, the filtrate is evaporated and the residue is shaken with 15 ml of ethyl acetate and 30 ml of water. The mixture is adjusted to pH 8.6 with 2 N aqueous sodium hydroxide solution, the aqueous phase separated and washed with 10 ml of ethyl acetate. The aqueous phase is adjusted to pH 4.25 with 4N hydrochloric acid and extracted three times with 10 ml of ethyl acetate each time. The combined extracts are dried and evaporated. The resulting 1- [N- (1-carboethoxy-3-phenylpropyl) -S-alanyl] indoline-2S-carboxylic acid has IR bands at 3210, 1745 and 1720 cm. [a] _D = -103.4 ° (c = 0.6 in ethanol).

Dissolve 0.6 g of the latter compound in 5 ml of diethyl ether and passes into the solution anhydrous hydrogen chloride. The resulting precipitate is filtered off, washed with diethyl ether and dried. The corresponding hydrochloride is obtained

at 176-180 ° melts.

Example 3 Analogously to the methods described here, the following l- (carboxy-azaaralkanoyl) -indoline-2S-carboxylic acids of the formula II are prepared:

No. R m R ' η R " IR (cm) or NMR (ppm) peaks 1 H O H 2 ^C 6 ^H 5 3225, 1740, 1715 2 H 1 H 1 ^C 6 ^H 5 1.35, 2.85, 4.80 3 H 3 (iso) H 2 ^C 6 ^H 5 1.15, 4.85, 7.9-7: i 4 H 4 (n) NH ₂ .2 ^C 6 ^H 5 2.95, 4.95, 7.95-7.1 5 5-CH ₃ 1 H 2 ^C 6 ^H 5 2.28, 4.72, 6.48 6 5-OCH ₃ 1 H 2 ^C 6 ^H 5 3.72, 4.80 7 5-OH 1 H 2 C ₆ H ₅ 3265 ₅ 2975, 1735 8th 5-Cl 1 H 2 ^C 6 ^H 5 4.90, 7.20, 8.21 9 H 1 H 2 PC ₆ H ₄ -Cl 3195, 1740, 1655

Example 4: A mixture of 5.0 g of 1- (S-alanyl) -indoline-2S-carboxylic acid, 22.0 g of 2-0xo-4-phenylbutanoic acid ethyl ester, 6.0 ml of triethylamine and 33.0 g of 3A Molecular sieve 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 3 hours. The reaction mixture is stirred at room temperature overnight, filtered and the filtrate evaporated to dryness. The residue is shaken with 30 ml of methylene chloride and 50 ml of water, adjusting the pH to 9 with 2 N aqueous sodium hydroxide solution. The aqueous phase is separated and washed with 30 ml of methylene chloride. The aqueous solution is adjusted 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. A product is obtained which consists mainly of the desired diastereoisomer. This is purified on a silica gel column by high pressure liquid chromatography. The eluent used is an 85:15 mixture of ethyl acetate and methanol. The 1- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] -indoline-2S-carboxylic acid is obtained. This product is dissolved in diethyl ether, treated with anhydrous hydrogen chloride and the resulting hydrochloride salt separated. The 1- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] -indoline-2S-carboxylic acid hydrochloride is obtained, which melts with decomposition at 140 °, [α] = -77.5 ° (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 2-0xo-4-phenylbutanoic acid ethyl ester, 22 g of diisoprop'ylethylamine and 130 g of 3A molecular sieve 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 5 hours. The reaction mixture is further stirred for one 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. The mixture is stirred for one hour and the pH is adjusted to 2.9 with 10% aqueous sodium hydroxide. The methylene chloride layer is separated and the aqueous phase is extracted twice more with 100 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The product obtained is recrystallized from 150 ml of ether. The 1- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] -indoline-2S-carboxylic acid is obtained, which melts with decomposition at 80 °. [a] _Q = -106 ° (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 2-0xo-4-phenylbutyrate and 6 ml of triethylamine in 115 ml of ethanol is dissolved in the presence of 4.8 g Raney nickel and 17 g of 3A molecular sieve hydrogenated at 2.7 atmospheres. After 15 hours, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is shaken with 75 ml of ethyl acetate and 50 ml of water, adjusting the pH to 8.6 with 2 N aqueous sodium hydroxide solution. The aqueous phase is separated off, washed with 20 ml of ethyl acetate, adjusted to pH 4.25 with 4N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined three last ethyl acetate extracts are dried over sodium sulfate and evaporated to dryness. The residue is treated with anhydrous hydrogen chloride in diethyl ether. The resulting hydrochloride salt is separated and recrystallized from ethyl acetate. The 1- [N- (1R-carboethoxy-3-phenyl-propyl) -S-alanyl] -indoline-2S-carboxylic acid hydrochloride, which melts at 207-208 °, is obtained [α] = -109.6 ° (c = 1.09 in ethanol).

Example 7: A mixture of 6.4 g of sodium 3-phenyl-2-oxo-pro.panoate, 2.0 g of l- (S-alanyl) -indoline-2S-carboxylic acid and 1.6 g of sodium cyanoborohydride in 50 ml of water is adjusted at room temperature with 1 normal hydrochloric acid to pH 7. The reaction mixture is stirred at room temperature for 2 days, quenched by the addition of 10 ml of concentrated hydrochloric acid and evaporated under reduced pressure. The product obtained is absorbed on a strongly acidic ion exchange column (Dowex 50, H form) and eluted with 4% aqueous ammonia. The 1- [N- (1-carboxy-2-phenyl-ethyl) -S-alanyl] -indoline-2S-carboxylic acid, which melts at 140-143 °, gives [α] = -92 ° (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 l- (S-alanyl) -indoline-2S-carboxylic acid, 13 g of 3A molecular sieve, 2.4 ml of triethylamine and 5.0 g of uric trienoic acid ethyl ester in 30 ml of ethanol becomes 30 Stirred minutes at room temperature. A solution of 0.54 g of sodium cyanoborohydride in 10 ml of ethanol is added over 2 hours. The reaction mixture is stirred at room temperature overnight, quenched with 4 ml of concentrated hydrochloric acid and evaporated to dryness. The product obtained is absorbed on a strongly acidic ion exchange column (Dowex 50, H form) and the column eluted with 4% aqueous ammonia. The 1- [N- (1-carboethoxy-ethyl) -S-alanyl] indole-2S-carboxylic acid is obtained, which has NMR peaks in DMSO at 3.8, 1.6 and 1.2 ppm.

Example 9: A solution of 0.5 g of 1- [N- (1-carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid in 25 ml of ethanol is saturated at 0 ° with ammonia and in a pressure vessel 4 days left. The solution is then evaporated, the residue. taken up in water, the mixture with 3N hydrochloric acid at 0 ° to pH 3.5 and extracted with methylene chloride. The 1- [N- (IS-carbamoyl-3-phenyl-propyl) -S-alanyl] -indoline-2S-carboxylic acid is obtained, which has peaks in the IR spectrum at 1710, 1660 and 3220 cm.

Example 10: Preparation of 10,000 tablets with a content of "5 mg of the active ingredient: Ingredients:

l- [N- (l-carboxy-3-phenylpropyl) -S-alanyl] -

indoline-2S-carboxylic acid. 50 g

Lactose 1157 g

Cornstarch 75 g

Polyethylene glycol 6000 75 g

Talcum powder 5 g

Magnesium stearate 18 g

Purified water - q.s.

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch 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 polyethylene glycol in 150 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 ° C, forced through a sieve of 1.2 mm mesh size and pressed into tablets of 6.4 mm diameter "having a score line.

Example 11 Preparation of 10'000 Capsules Containing 10 mg of the Active Substance:

ingredients:

l- [N- (lS-carboethoxy-3-phenylpropyl) -S-alanyl] -

indoline-2S-carboxylic acid. 100 g

Milk sugar - 1800 g

Talcum powder 100 g

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with talc and subsequently with lactose in a suitable mixer. Capsules no. 3 are filled with 200 mg of the mixture each with a filling machine.

Analogously, tablets or capsules are prepared from other compounds of the invention, e.g. those exemplified herein in the further examples.

Example 12: A mixture of 1- (S-alanyl) -indoline-2S-carboxylic acid (loo g), 2000 ml of anhydrous ethanol, 29.9 g of acetic acid and 270 g of ethyl 4-phenyl-2-oxo-butanoate becomes 2 Stirred at room temperature for hours. Then, within 5 hours, 33.3 g of sodium cyanoborohydride in 300 ml of anhydrous ethanol, evenly, keeping the temperature between 20-24 °. The reaction mixture is stirred overnight at room temperature, then cooled to 0 °, mixed with 100 ml of 12-molar hydrochloric acid at once and the cooling is interrupted. The mixture is stirred for 1 hour and then evaporated at 3 mm Hg and 20-24 °. The resulting syrup is added to a vigorously stirred mixture of 600 g of ice, 600 ml of 6N sodium hydroxide, and 1000 ml of ether. The aqueous phase is separated and washed with 1000 ml of fresh ether. The aqueous solution (pH about 1.24) is treated with 1000 ml of methylene chloride, cooled to 0-5 ° and acidified quickly with about 93 ml of 12 N hydrochloric acid to pH 4.3. The methylene chloride is separated and the aqueous mixture extracted twice with 500 ml of methylene chloride. The combined organic solutions are dried over anhydrous sodium sulfate, clarified by filtration and evaporated at 20-24 ° and 3 mm Hg. The 1- [N- (IS-carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid is obtained as a foam.

Dissolve 194 g of the crude base obtained in.500 ml of ethyl acetate and the solution is added dropwise to a vigorously stirred solution of 42 g of phosphoric acid in 2300 ml of ethanol. The mixture is kept at 5 ° overnight, then stirred for one hour and the precipitate filtered off. The filter cake is washed 3 times with 100 ml of ethyl acetate and 3 times with 100 ml of ether and dried at 24 ° and 3 mm Hg. The crude phosphate salt obtained is recrystallized from a mixture of absolute ethanol / ethyl acetate and dried at 24 ° and 0.01 mm Hg. One obtains the 1- [N- (IS-

r \ -j fS & BB «S ⁷ Q * w§7 ygg / ¹ ^ iB * 0

Carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid 1: 1 phosphate, which melts at 125-129 °

[α] ^ ³ = -87.2 ° (c = 1 in methanol).

Example 13: A solution of 3.67 g of sodium hydroxide in 100 ml of ethanol at room temperature [N- (lS-carboethoxy-3-phenylpropyl) -S-alanyl] with a suspension of 16.0 g of "1- -indoline-2S 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 off with diethyl ether washed and dried in vacuo to give the sodium salt of 1- [N- (1-carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid, mp 190-192 °. [et] = -110 ° (c = 0.2 in ethanol).

Example 14 : 1.6 g of sodium hydroxide in 50 ml of water are added to 8.0 g of 1- [N- (1S-carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid in 50 ml of methanol. The reaction mixture is stirred for 3 hours at room temperature and then evaporated The residue is taken up in 100 ml of water and extracted twice with 50 ml of diethyl ether each time The aqueous layer is adjusted to pH 3 with concentrated hydrochloric acid The precipitate is filtered off and recrystallized from ethyl acetate to give the 1- [N- (IS-carboxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid, which melts at 159-160 °, [α] = -70.4 (c = 0.6 in ethanol).

Example 15 : A solution of 3.0 g of sodium l- [N- (1S-carboethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid salt in 30 ml of methanol containing 100 mg of sodium carbonate becomes 10 Cooked under reflux for a few hours and then evaporated. The residue is dissolved in 150 ml

-28- L · M ^m i U-UM

Diethyl ether was added and filtered. The filtrate is evaporated to a volume of 50 ml and treated with 50 ml of hexane. The resulting precipitate is filtered off. The 1- [N- (IS-carbomethoxy-3-phenylpropyl) -S-alanyl] -indoline-2S-carboxylic acid sodium salt, melting at 140-145 °, is obtained [α] = -123.7 ° (c = 0.8 in methanol).

Starting material for example 3/3

A solution of 5.0 g of indoline-2S-carboxylic acid ethyl ester hydrochloride, 5.5 g of N-carbobenzyloxy-L-valine and 3.0 ml of triethylamine in 200 ml of methylene chloride is mixed with 4.4 g of l (3 Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture is stirred overnight at room temperature and then washed with 75 ml of water, 75 ml of 2 N aqueous hydrochloric acid and 75 ml of saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated. The 1- (N-carbobenzyloxy-L-valyl) -indoline-2S-carboxylic acid ethyl ester is obtained.

9.3 g of 1- (N-carbobenzyloxy-L-valyl) -indoline-2S-carboxylic acid ethyl ester in 75 ml of methanol are mixed with 1.05 g of sodium hydroxide in 75 ml of water. The reaction mixture is stirred at room temperature for 3 hours and then evaporated. The residue is taken up in 200 ml of water and washed with 75 ml of methylene chloride. The aqueous layer is concentrated with 5 ml. Acidified hydrochloric acid and then extracted three times with 75 ml of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The 1- (N-carbobenzyloxy-L-valyl) -indoline-2S-carboxylic acid is obtained.

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 catalyst. The reaction mixture is at room temperature

-29- £ ti ¹ I y U IJ 1

and atmospheric pressure for 3 hours hydrogenated and evaporated. The 1- (L-valyl) -indoline-2S-carboxylic acid is obtained. which melts at 194-196 °.

[α] = -63.2 ° (c = 0.9 in 50% aqueous ethanol).

Starting material for example 3/4

To 10.0 g of indoline-2S-carbonsäureäthylester, 10.7 g of aNt-butoxycarbonyl-t -.- N-benzyloxycarbonyl-L-lysine and 6.1 ml of triethylamine in 250 ml of methylene chloride are added 8.8 g l (3 dimethylaminopropyl) -3-äthylcarbodiimid hydrochloride. The reaction mixture is stirred at room temperature overnight, washed with 75 ml of water, 75 ml of 2 N aqueous hydrochloric acid and 75 ml of saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated. This gives the 1- (a-N-t-butoxycarbonyl-C-N-benzyloxycarbony1-L-lysyl) -indoline-2S-carboxylic acid aryl ester.

A solution of 22.5 g of - (a-N-t-butoxycarbonyl-f-N-benzyloxycarbonyl-L-lysyl) -indoline-2S-carboxylic acid ethyl ester in 150 ml of methanol is treated with 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 is taken up in 300 ml of water and washed with 100 ml of methylene chloride. The aqueous layer is concentrated with 5 ml. Acidified hydrochloric acid and extracted three times with 100 ml of methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated. The 1- (α-N-t-butoxycarbonyl-C-N-benzyloxycarbonyl-L-lysyl) -indoline-2S-carboxylic acid is obtained.

To 7.6 g of l-Ca-N-t-butoxycarbonyl-'t-N-benzyloxycarbonyl-L-lysyD-indoline-2S-carboxylic acid in 13 ml of glacial acetic acid, 20 ml of methylene chloride and 13 ml of anisole are added at 0 ° 40 ml of T.rifluoroacetic acid. The reaction mixture is allowed to warm to room temperature with stirring for 30 minutes and then evaporated. The residue is recrystallised from diethyl ether.

, - 30 -

Siert. The trifluoroacetic acid salt of 1- (t-N-benzyloxycarbonyl-L-lysyl) -indoline-2S-carboxylic acid is obtained.

Cardiovascular pharmacology of compounds of the invention

The test of the effect of compounds has been carried out according to the methods for the evaluation of the inhibition of the enzyme which converts angiotensin [angiotensin converting enzyme = ACE]. The biochemical assessment of in vitro ACE inhibition (ACEI inhibition = ACEI) determines the activity of a compound in rabbit lung tissue.

In the in vivo test method, an increase in blood pressure is first caused by administration of angiotensin I (AI) to the test animal. It is then measured the inhibition of the individual compounds on this blood pressure increase.

I. Biochemical test method

A rabbit lung tissue preparation ['(Das and Saffer, J. Biol. Chem. 250 : 6762 (1975)] was used for the determination of ACE by the method of Cheung and Cushman [Cheung and Cushman, Biochim. Biophys 293 , 451 (1973)] In this method, the amount of histidyl leucine released from a synthetic substrate within a 30 minute * incubation at 37 ° C is determined spectrophotometrically The IC values of ACE inhibition The IC value is then the concentration (in moles) of compound tested which reduces the amount of histidyl leucine produced in the absence of the test substance by 50%.

II. Method of Inhibition of Angiotensin I (AI) Induced Blood Pressure Increase by Intravenous Administration of the Test Compound (% AI Inhibition)

In these studies, as described above, one catheter each is inserted into a femoral artery and into a calf vein of the rat.

The arterial pressure was from. from the arterial catheter while injecting angiotensin I (AI) and the individual test compounds through the venous catheter. The inhibition of angiotensin I induced blood pressure increase is reported in the table as an average value 30 minutes after the administration of selected doses of the respective compound. In this case, such dosages are selected so that u.a. the "ID (i.v.) value can be determined.

Results:

Connection of the In vitro ACEI Inhibition of angiotensin I (AI) induced blood pressure increase % AI inhibitions example IC (M) iv Dose (mg / kg) 80 1 -9 6 χ 10 0.1 35 6 8 χ 10 ~ ⁶ 0.1 80 7 3 χ 10 ~ ⁸ 1.0 95 "80 33 4 3 χ 10 ⁷ 0.1 0.06 0.03

Claims (9)

1) a Schiff'sehe base of the general formula III 2, process according to item 1, characterized in that compounds of the formula I shown in point 1, in which Ph is unsubstituted 1,2-phenylene or by one or two, identical or different substituents of the group lower alkyl, -lower alkoxy, hydroxy and halogen, or by an alkylenedioxy or trifluoromethyl-substituted 1,2-phenylene, R ₁ is hydrogen, lower alkyl or u> -Amine- lower alkyl, R _p Lower "means alkyl or cj '-HPh-lower alkyl, and each of the _{4β 5β} 1982 AP C 07 D / 234 586/1 - 35 - 60 053/12 Symbols R.sup.1, R.sup.2 and R.sup.3 represent hydrogen or lower alkyl, their amides, mono- or di-lower alkylareas, lower alkyl esters "(amino _s mono- or di-lower alkylarnino, carboxy or carbo-lower alkoxy) -lower alkyl esters and salts 2) a compound of general formula IV (IV) COOH or their functional derivatives mentioned, with a reactive functional derivative of a compound of general formula V Y-CH-COOH I ^R 2 * in which X is hydrogen and Y is for the grouping HOCO-CHR-N-COOR wherein R is t-butyl or benzyl; or 1 ο ο X is CO-CHR-Z and one of the symbols Y and Z represents amino and the other represents a reactive esterified hydroxy group, 'condenses' and converts said COOR group to hydrogen, or 3, process according to point l _f, characterized in that compounds of the formula I shown in point 1, wherein Ph is an optionally monosubstituted by lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogen or trifluoromethyl 1 ^ -phenylene, R _{1 is} lower alkyl or < JJ-amino-lower alkyl, R "is lower alkyl or -HPh w-lower alkyl, and each of the symbols R, R, and R is hydrogen or methyl, their Amidejf mono- or di-niederalkylamide, Niederalkyiester ^ (Aminoj mono- or di lower alkylamino, carboxy or carbo-lower alkyl) lower alkyl esters and salts. » 4 _e method according to item 1, characterized in that.man compounds of general formula II CH COOH CH ₀ -R * (CH ₀ ) -R "m 2ra ^v 2'n wherein R is hydrogen _{t is} alkyl or alkoxy having at most 4 carbon atoms each, hydroxy, halogen or trifluoromethyl * γβ is an integer from 1 to 4 S ₃ W " WUW i 3) a compound of general formula VI. \ C-R NV
I * CO-CH-NH-CH-W 1 IR ₁ R ₂ wherein at least one of the symbols V and W is cyano, and the other is the said free, amidated or esterified carboxy group, hydrolyzed or alcoholized, or 4.5,1982 AP C 07 D / 234 586/1
- 36 - .60 058/12 η is an integer from 1 to 3, R 'is hydrogen or amino, and R "is hydrogen or R ~ phenyl, their mono- or bis-amides, the mono- or
Bis (lower alkyl or & J -amino-lower alkyl) esters, and
Salts, produces, 4) in a compound of general formula VII CO-CH-NH-CH-COOH
II
R ₁ R ₂ or in their said functional derivatives, hydrogenating the indole moiety to the indoline moiety and, if desired, converting a compound obtained into another compound of the invention, and / or, if desired, a resulting free compound in a salt or a salt obtained in the transferred free compound or into another salt, and / or, if desired, a resulting mixture of isomers or racemates in the individual isomers or Razemate separates, and / or, if desired, received Razemate in the optical antipodes splits « 4,5.1982 AP C 07 D / 234 586 / i - 34 - 60 058/12 4,5.1982 AP C 07 D / 234 586/1 32a - 60 058/12 (III) COOH CO-C (H) C = N) C (H) -COOH
R ₁ R ₂ - 33 - or their functional derivatives mentioned, wherein one of the symbols ρ and q is zero and the other is 1, hydrogenated, or 4.5 * 1982 AP C 07 D / 234 586/1 - 32 - 60 058/12 ErfinduηαsaηsDruch A process for the preparation of novel l ~ carboxy ~ (aza-.alkanoyl or azaaralkanoyl) ~ indoline ~ 2-carboxylic acids of general formula 1 COOH
Co-CH-NH-CH-COOH wherein Ph is unsubstituted 1,2-phenylene or by one to three identical or different substituents of the group lower alkyl, lower alkoxy, lower alkylenedioxy * hydroxy, halogen or trifluoromethyl substituted 1,2-phenylene, _t R * is hydrogen _Λ lower alkyl, or amino-lower alkyl _t R _{2 is} lower alkyl or HPh lower alkyl, and each of R, R and R is hydrogen or lower alkyl; their amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carboxy-lower alkoxy-lower alkyl esters, and their salts, characterized in that 5. The method according to item 1, characterized in that one compounds aer in the formula shown in point 4 in the II
Form their indoline ~ 2S-carboxy chiral epimers
establishes " 6 «method according to item 1, characterized in that 1_ ^ N- (I-carboxy ~ 3-phenylpropyl) ~ S ~ alanyl3 ~ indolin» 2S-carboxylic acid and its salts are prepared, 7, method according to item 1, characterized in that one prepares 1- £ N ~ (lS-Carboethoxy ~ 3 ~ phenylpropyl) ~ S-alanyl3 ~ indolin «2S ~ carboxylic acid and its salts. 8, process according to item 1, characterized in that 1-CN - "(1R-carboethoxy-3" phenylpropyl) "S-alanyl-J" 'indoline ™ 2S-carboxylic acid and its salts are prepared, Method according to item 1, characterized in that 1-CN- (1-carboxy-2-phenylethyl) -S-alanyl-3-indoline-2S-carboxylic acid and its salts are prepared.