NO813694L - 1-CARBOXY-AZAALKANOYLINDOLINE-2-CARBOXYL ACIDS, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS, AND THEIR THERAPEUTIC APPLICATIONS - Google Patents

Description

1-Alkanoylindoline-2-carboxylic acid and their 5,6-dihydroxy derivatives, namely the N-acylated cyclodopa derivatives, are disclosed in Nippon Kagaku Zasshi 87, 760 (1966), in US Patent 3' 796 723, resp. 1 Raise. Chlm. Acta 53, 1701

(1970), e.g. as examples for the synthesis of O- and/or N-acyl compounds. Also 1-(carboxy-azaalkanoyl or azaaralkanoyl)-(azetidine, pyrrolidine or piperidine)-2-carboxylic acids and their functional derivatives are e.g. known from European patent, 0012 4-01 as compounds with antihypertensive action.

It has now surprisingly been found that either by introducing a carboxy group and an azadel into the above-mentioned indolines or by expanding the above-mentioned pyrrolidines into indoline ring systems, superior antihypertensive agents are obtained.

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

in which Ph means unsubstituted 1,2-phenylene or 1,2-phenylene substituted with one to three equal or different substituents from the group of lower alkyl, lower alkoxy, lower alkylene-dioxy, hydroxy, halogen or trifluoromethyl, R. means hydrogen, lower alkyl or amino-lower alkyl , R ? means lower alkyl or HPh-lower alkyl, and each of the symbols Ry and R,, means hydrogen or lower alkyl, as well as their amides, mono- or dilower alkylamines, lower alkyl esters, (amino, mono- or dilower alkylamino, carboxy or carbon-lower alkyl oxy)-lower alkyl esters, . and their salts, especially their therapeutically useful salts, as well as processes for their preparation, pharmaceutical preparations containing

these compounds, as well as their therapeutic application.

The 1,2-phenylene group Ph and/or the phenyl group HPh

is preferably unsubstituted or monosubstituted. Their substituents can be illustrated by the following groups: Lower alkyl, e.g. methyl, ethyl, n- or isopropyl or -butyl, lower alkoxy, e.g. methoxy, et.oxy, 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 Rg is preferably methyl, ethyl, n- or isopropyl or -butyl. The amino-lower alkyl group R^ preferably means oo-amino-(ethyl,

propyl, butyl or pentyl), and the aryl lower alkyl group is also preferably HPh-methyl or w-HPh-(ethyl or propyl).

Each of the symbols R-^ in R^ and R^ preferably means hydrogen, but also lower alkyl, preferably methyl, or another above-mentioned lower alkyl group.

The term "lower" in the above-mentioned and following mentioned organic residues optionally defines such compounds with a maximum of 7, preferably 4, especially 1 or 2 carbon atoms.

Said functional derivatives in which either one or the two carboxy groups are esterified or amides are preferably mono- or bis-lower alkyl esters, e.g. methyl, ethyl, n- or isopropyl or -butyl ester, mono- or bis-amides, or the corresponding N-alkylated amides, e.g. mono- or dimethylamine. The mentioned substituted lower alkyl esters are preferably half esters with free indoline-2-carboxy groups, e.g. co -(amino,.mino- or dimethylamino, carboxy, or carbethoxy)-(ethyl, propyl or butyl)-esters.

Salts are preferably therapeutically applicable salts, e.g. metal or ammonium salts of the aforementioned acids, especially alkali metal or alkaline earth metal salts, e.g. sodium-potassium-,. magnesium or calcium salts, primarily easily crystallising, ammonium salts. These are derived from ammonia or organic amines.;-:f. e.g. mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylene diamines or (hydroxy lower alkyl or aryl lower alkyl) lower alkyl ammonium bases, e.g. methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrimethylammonium hydroxide. The mentioned basic (amino, mono or dilower alkylamino) lower alkyl esters also form acid addition salts. These are preferably prepared with acids which give therapeutically usable acid addition salts. Acids which give therapeutically useful acid addition salts

is e.g. inorganic acids such as halogen hydrogen, e.g. hydrochloric or hydrobromic acid, or sulphurous, phosphoric, nitric or terchloric acid, or preferably organic acids, such as aliphatic or aromatic carboxylic acids, or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic

acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, hydroxymaleic acid, grape acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, A-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid,. sulf aEiil acid - - or r cyclohexyl sulf amic acid or ascorbic acid..

The compounds produced according to the invention

shows valuable pharmacological properties, primarily hypotensive, antihypertensive and bradycardic effects,

which evokes a. due to their inhibitory effect on

the enzyme that converts angotensin. These pharmacological properties can be demonstrated by means of in vivo or in vitro animal experiments on mammals such as rats, cats, dogs or their isolated organs, as test subjects. The animals can be either normotensive or hypertensive, e.g. genetically hyper-tensive ■.rats, or renal hypertensive rptters or dogs, and dogs, from which sodium is . been removed. The compounds mentioned can be administered enterally or parenterally,

preferably orally or intravenously, e.g. by means of gelatin capsules or in the form of a starchy suspension,

respectively aqueous solutions.. The dose used may lie in a range approximately between 0.051 mg/kg/day, preferably approximately 0.1 and 25 mg/kg/day, especially approximately 1 and 10 mg/kg/day.

The in vivo blood pressure-lowering effect is recorded either directly with a catheter, such as e.g. is introduced into the dog's femoral arteries, or indirectly by saliva monomanometry on the rat's tail, and a transfer instrument. The blood pressure is determined before and after administration of the active substance in mmHg. Thus, e.g. de-representative compounds according to the invention which are illustrated in the examples very effective in hypertensive rats or dogs, already when administered in small oral doses in mg/kg/day, and lower.

The new compounds also show an inhibitory effect

on the response of blood pressure in normotensive rats to angiotensin I. Under normal conditions, the enzyme renin causes a specific hydrolysis of the circulating renin substrate protein. This hydrolysis gives angiotensin I, which is further hydrolysed to the strongly vasoconstricting • angiotensin II by the action of the aforementioned enzyme which converts angiotensins. Inhibition of the aforementioned system prevents the formation of angiotensin

II of I. This hemmin therefore dampens any •reaction of the blood pressure after an angiotenih-I attack.

The corresponding in vivo test is carried out with male normotensive rats that are . anesthetized with 100-120 mg/kg intraperitoneally administered sodium salt of ethyl-(1-methyl-propyl)-malonylthiourea. A femoral artery and a femoral vein are each equipped with a puncture needle for the direct measurement of the blood pressure and for the intravenous administration of angiotensins I and compounds according to the invention. After stabilization

of the basal blood pressure, the pressure change is determined in three during 5-minute intervals carried out irritations with 0.33VJg/kg angiotensin I i.v. Pressure changes are also determined 5»10, 15»30 and 60 minutes after either intravenous or oral administration (by gastric tube) of the compounds which

must be investigated. The latter pressure changes are compared with the initial values. Any determined decrease in blood pressure response is a reference to inhibition of the enzyme that converts angiotensin. This decrease can be up to 80% after doses of 10 mg/kg i.v. or 50 mg/kg p.o. and lasts up to 60 minutes.

The in vitro inhibition ..of. the enzymes that convert angiotensin can be detected by the compounds produced according to the invention analogously to biochim. Biophys. Acta 293»4-51 (1973) According to this method, said compounds are dissolved in approximately 1 mmol concentrations in . f o.sf atpuf f ere, which is cooled from the outside with ice. To these solutions, one first puts different µl amounts of 1 mMolar histidyl-leucine in phosphate buffer and then 100 µl of 5 mMolar hippuryl-histidyl-leucine in phosphate buffer and 50 µl of the angiotensin-forming enzyme. This enzyme is prepared fresh from the lungs of adult male rabbits in tris buffer, which contains potassium magnesium chloride and also cane sugar. The mentioned solutions are incubated for 4-0 minutes at 37UC, and the reaction is further stopped by the addition of 0.75 ml of 0.6 N sodium hydroxide solution. Then, at room temperature, 100 µl of p-ptalaldehyde and, after 10 minutes, 100 µl of 6-nermal hydrochloric acid are added. The samples are compared in a spectrophotometer at 360 nm with water, and their optical density is determined. These values are adapted with the help of a conversion factor to a standard curve, obtaining a below-mentioned incubation of 4-0 minutes formed amounts of histidyl-leucine in nanomoles. The results are displayed graphically as a curve to determine the IC value in relation to the effective substance concentration. This ve.rdl means the active substance concentration that gives half the activity of a control sample that does not contain active substance. The mentioned representative compounds produced according to the invention are also very effective in this in vitro test system, up to the IC^ value of 39 nM and lower.

Consequently, the compounds produced according to the invention are valuable antihypertensive agents, especially for lowering high blood pressure (regardless of etiology) and/or in heart diseases such as heart failure, and/or other conditions associated with edema or ascites, e.g. liver cirrhosis. They can also be used as intermediates for the production of other valuable products, especially pharmacologically active preparations.

Preferred compounds are those of formula I in which Ph means unsubstituted i. 1,2-phenylene, or 1,2-phenylene substituted with one or two identical or different substituents from the group of lower alkyl, lower alkoxy, hydroxy and halogen, or with a alkylenedioxy or trifluoromethyl group, R.j means hydrogen, lower alkyl or co-aminolower alkyl, R- means lower alkyl or co-HPh-lower alkyl, and each of the symbols R^, R^ and R^ means hydrogen or lower alkyl, as well as their amides, mono - or di-lower alkyl amides, lower alkyl esters (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkyl oxy)-lower alkyl esters and salts, especially therapeutically useful alkali metal-alkaline earth metal ammonium salts or acid addition salts.

Further compounds of formula I are preferred in which Ph means an optionally lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogen or trifluoromethyl monosubstituted 1,2-phenylene, R^ means lower alkyl or co-aminolower alkyl, R^ means lower alkyl or co-HPh-lower alkyl . especially therapeutically useful alkali metal, alkaline earth metal, ammonium or acid addition salts.

Particularly to be highlighted are the compounds of the general formula II, especially their indoline-2S-chiral epimers, in which R means hydrogen, alkyl or alkoxy with a maximum of 4 carbon atoms each, hydroxy, halogen or trifluoromethyl, m means an integer from 1 to 4",, n is an integer from 1 to 3, R' means hydrogen or amino, and R" means hydrogen or R-phenyl,

as well as their mono- or bisamide, mono- or bis-(lower alkyl or co-amino-lower alkyl) esters, and salts, especially therapeutically useful alkali metal, ammonium or acid addition salts.

Particularly preferred are the compounds of formula II, in which R means hydrogen, methyl, methoxy, hydroxy or

chlorine, preferably in the 5-position, m means 1, n means the number 2, R' means hydrogen, and R" means phenyl, as well as their mono- or bisamine, their mono- or bis-(lower alkyl or co-amino-lower alkyl) -esters, and salts, especially therapeutically useful alkali metal, ammonium salts, or acid addition salts.

The compounds according to the invention are prepared

in a manner known per se by that

1) a naval base with the general formula III

or their mentioned functional derivatives in which one of the symbols p and q means 0, and the other 1, is hydrogenated or 2) compound of the general formula IV or their mentioned functional derivatives is condensed with a reactive derivative of the compound of the general formula V in which X means hydrogen, and Y the group HOCO-CHR^-N-C00Rq, wherein Rq means t-butyl or benzyl, or X means CO-CHR^Z and one of the symbols Y and Z means amino, and the other a reactive esterified hydroxy group, and the said C00Ro group is converted to hydrogen, or 3) a compound of the general formula VI in which at least one of the symbols V and W means cyan, and the other means the said free, amidated or esterified carboxy group, is hydrolyzed or alcoholized or U) in a compound of the general formula VII

eHere in their mentioned functional derivatives, the indole part is hydrogenated to the indole part, and if desired, a compound formed is converted into another compound according to the invention.

The hydrogenation of the compounds of formula III is carried out according to methods known per se, e.g.

either with catalytic activated or nascent hydrogen such as hydrogen in the presence of platinum, palladium or nickel catalysts, or with electrolytically produced 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, can be used.

Fractionable functional derivatives of compounds of formula V are preferably ester halides,

simple or mixed anhydrides, e.g. lower alkyl half-esters of the aforementioned acid chlorides, 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 aforementioned condensation of the compounds III and IV proceeds either spontaneously or in the presence of condensation agents, e.g. organic or inorganic bases having the aforementioned salt-forming amines or alkali metal carbonates or di-substituted carbodiimides. In a compound formed which contains the aza-protecting group C00Rq, the latter can be cleaved according to those from peptide chemistry in well-known methods, preferably by means of the catalytic hydrogenation mentioned earlier or by the hydrolysis mentioned below. The starting materials mentioned are also known, or if they are new, they can be prepared according to method 2) analogous to

condensation on.

The hydrolysis of nitrml 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 mentioned alcoholysis is carried out analogously in the presence of the mentioned acids, and the corresponding unsubstituted or substituted lower alkanols.

Finally, the aforementioned hydrogenation is carried out

of indoles VII to the indolines I also according to the usual hydrogenations of 1-acylindolines, e.g. with catalytically activated or nascent hydrogen, such as hydrogen in the presence of platinum, palladium, rhodium or nickel catalysts, or with electrolytically produced hydrogen, or by the action of the 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 can be used. An asymmetric one is preferred. hydrogenation to the indoline-2S-carboxylic acid and their aforementioned derivatives. Chiral catalysts are thereby used, e.g. such as are prepared from a rhodium salt, with (R)-1,2-bis-(diphenyl-phosphino)-propane or (R)-1,2-bis-(o-anisylphenylphosphino)-ethane and 1,5-cyclooctadene .

Functional derivatives of carboxylic acid, e.g. of those with formula, III, IV, V, VII, RgCOCOOH are. preferably esters, e.g. lower alkyl esters, such as ethyl, t-butyl or aralkyl esters, e.g. benzyl ester.

By a reactive derivative of a carboxylic acid is preferably meant here acid halides, reactive esters, simple or mixed anhydrides, or similar compounds known from the state of the art, such as those mentioned for formula V.

The starting materials are known or, if they are new, can be prepared according to methods known per se, for example analogously to those mentioned in the examples. New starting materials are also covered by the invention.

Starting substances of formula III are prepared step by step in situ, by condensation of a compound of formula IV, in which X means the group R^COCO with a compound R2CHNH2COOH or one of their functional derivatives. They can also be obtained by condensation of compound IV in which X means the group R^CHNHgCO with a compound of formula R^COCOOH or one of their functional derivatives. The condensations are carried out in an inert solvent in the absence or presence, e.g. of an 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 in which X means the group R^COCO are known, or can be obtained by condensation of the compound of formula IV, or an ester thereof,

wherein X means hydrogen, with an optionally protected (e.g. dithioketal) compound of formula R^COCOOH, or one of its reactive functional derivatives.

Intermediates of formula IV, in which X means R^CHNHgCO are prepared by condensation of a compound of formula IV, or one of its esters, in which X means hydrogen with an optionally N-protected (e.g. N-benzyloxycarbonyl, or t-butyloxycarbonyl derivative ) compound with formula R^CHNH^COOH or one of their reactive functional derivatives. If necessary, the protected group can later be released again in a manner known per se, or as discussed below. The condensations mentioned above or in the following with reactive functional derivatives of carboxylic acids proceed spontaneously or in the presence of condensation agents, e.g. inorganic or organic bases such as potassium carbonate, pyridine or triethanolamine. The condensations of the carboxylic acids in and of themselves can be carried out in the presence of a coupling agent, e.g. dicyclohexyl carbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

The compounds of formula IV in which X means the group C0CHR.J Z can be prepared by acylation of a compound of formula IV, in which X means hydrogen with a functional derivative a.v HOCOCHR^Z, in which Z means a reactive esterified hydroxy group (e.g. chlorine or tosyloxy) or a protected amino group, e.g. t-butyloxycarbonylamino-(t-BOC-amino) or carbobenzyloxyamino (Cbo-amino), and the transfer to the compounds of formula IV, in which X means the group COCHR^NH^ according to methods known per se and discussed below, e.g. hydrolysis under acidic conditions or catalytic hydrogenation.

Compound of formula V in which Y means;.H0C0-CHR1-N-C00Rq_,_ can preferably be prepared as follows: a) Reaction of an ester (e.g. lower alkyl ester as t-butyl ester)" has the compounds of formula R^CHNH^ COOH with an ester (eg, lower alkyl ester, such as ethyl ester) of a compound of formula R^CO-COOH, in the presence of a dehydrating agent, eg, boron trifluoride.

b) Reduction of the formed Schiff's base according to methods known per se, X'f. e.g. by hydrogenation i

presence of palladium or nickel catalysts or with a reducing agent, e.g. sodium cyanoborohydride.

c) Protection of nitrogen in the formed azadiester with a known reactive functional derivative of RqC00H

and

d) Hydrolysis of formed N-protected diester of a compound of formula V, in which Y means H0C0-CHR1-N-C00Rq.

Starting substances of formula VI in which W means cyan can preferably be prepared starting from a compound of formula IV, in which X means C0CHR^NH2, and a compound of formula R2CHY-CN, in which Y means a reactive esterified hydroxy group. Starting substances with formula VII can be obtained according to method 2) as previously discussed.

In this method, a compound is replaced by formula

IV with the corresponding indole compound, in which instead of R^ and R^ a single bond is present, connecting the carbon atoms having the residues R^ and R^.

The formed compounds according to the invention can be transferred in a manner known per se into other compounds according to the invention. Thus, e.g. formed amides or esters are further hydrolysed or!• alcoholysed (transesterified). This can be done according to method 3)» or with aqueous alkalis, e.g. with alkali metal carbonates, resp. -hydroxides.. Formed free acids can on

in a manner known per se, is esterified with the aforementioned unsubstituted or substituted lower alkanols or diazoalkanes, or converted into the aforementioned metal ammonium or acid addition salts.

Thus, e.g. a formed free (amphoteric) compound is converted into a corresponding metal, ammonium or acid addition salts by reaction with an equivalent amount of corresponding base of one basic salt, an acid or an ion exchanger. The aforementioned acids are thereby treated with alkali metal or ammonium hydroxides or carbonates, and the aforementioned acids, amides or esters with the above-mentioned inorganic or organic acids. A formed salt can also be transferred to the free compound when treated with stronger acids, resp. bases, preferably, with a Ph-value between 3 and 5.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the preceding and following with free compounds (or intermediates) and salts, also, and understand possibly the corresponding salts resp. free connection.

Formed geometric . or opjbic isomer mixtures of the above-mentioned compounds with the formulas I to VII can be separated in a manner known per se, e.g. by fractional distillation, crystallization and/or chromatography in the individual isomers. Racemic products can be resolved in the optical antipodes, e.g. by separation of their diastereomeric salts, which according to J, Org. Chem.

4-3» 3.803 (1978), e.g. by fractional crystallization of d- and 1-(tartrates, mandelates, camphor sulphonates or 1-naphthyl-1-ethyl isocyanate), or of d- and l-(a-methyl-benzyl-

ammonium, cinchonidine, chinhonin, quinine, quinidine, ephedrine, dehydroabiethylamine, brucine or strychnine) salts. The preferred starting materials of formula III are its 2S optical isomers (epimers).

The above-mentioned reactions are carried out according to methods known per se in the presence or absence of diluents, preferably in those which are inert to the reagents and dissolve these catalysts alkaline or acidic condensation or other above-mentioned agents, e.g. the usual agents used to protect the amino groups in peptide synthesis, and/or in an inert atmosphere under 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 modification

of the present process according to which an intermediate formed at one or another stage of the process is used as starting material, and the remaining process steps are carried out, or the process is interrupted at one or another stage, or according to which a starting material is formed under the reaction conditions or-in which a starting material is used in the form of a salt or optically pure antipodes.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned above as particularly valuable, especially those with the formula 'IT^.rig. are the following chiral isomers:

The pharmacologically useful compounds prepared according to the invention. can be used for the production of pharmaceutical preparations containing an effective amount of the active substance together or in a mixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactaose, dextrose, cane sugar, mannitol, sorbitol, cellulose, and/or glycine and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch pastes, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and if desired explosives, e.g. starches,.. agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of binders, and/or fizzy mixes or adsorbents, coloring substances, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories primarily fat emulsions or suspensions.

The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure, and/or buffers. The pharmaceutical preparations which, if desired, can contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g.

using usual mixing, granulating or coating methods, and contains from approx. 0.1% t 'to approx. 75%, especially from approx. 1% to approx. 50% of the active substance. Single doses for mammals with a weight of approximately 50-70 kg can contain between approx. 5 and 500 mg of the active ingredient

share.

The invention will be explained in more detail with the help of some examples. The temperatures are stated in degrees Celsius, and the indication above parts relates to parts by weight. When nothing else is defined, the injection of solvents is carried out under reduced pressure, e.g. between approximately 15 and 100 mm/Hg.

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 adjusted at room temperature with aqueous sodium hydroxide solution at a pH value of 7 ,5. The mixture is mixed with 0.8 g of crude sodium cyanoborohydride, and stirred overnight at room temperature. The mixture is then dissolved with 5 ml of concentrated hydrochloric acid, and filtered through a short column of a strong ion exchange resin ("dowex'<r>50 W - X4-).. The column is first eluted with 50% lg aqueous ethanol (removal of the starting material and then with 4-$-ig (volume) aqueous ammonia. The latter eluate is evaporated, the residue is slurried in 6:ml water, whose pH-yerdi with 1- normal hydrochloric acid.is adjusted to 3, and the precipitate formed is collected. 1-/N-(1-carboxy-ysy-3-phenylpropyl)-S-alanyl/-indoline-2S-carboxylic acid of formula II is obtained, in which R =R'=H,''M = 1, n = 2, and R" = C^H^. Sm.p. U0-U6°C, /<o>7D<=><->96° (c = 0.8 in ethanol).

Starting materials are prepared as follows: 120 g of 1-acetyl-indoline-2-carboxylic acid (Nippon Kagaku Zasshi 87," 760 (1.966')_7 and 172 g of 1-cinchonidine are dissolved in 1,200 ml of hot ethanol. The solution is prepared by room temperature overnight, and then for 4 days at 0° C. The white crystalline salt is filtered off and removed. The filtrate is evaporated, mixed with 1000 ml of water, and the solution is adjusted with concentrated hydrochloric acid to a pH value of 1. After 15 minutes, the product is filtered off , washed 3 times with 250 ml of 2-normal hydrochloric acid, 2 times with 500 ml of water,,

and 2 times with 100 ml" ethanol. 1-acetyl-indoline-2S-carboxylic acid is obtained, which melts at 214.-215°C f<a>JB= -133.3°

(c = 1.165 in ethanol).

A suspension of 37.5 g of the latter compound in 380 ml of 2-normal aqueous hydrochloric acid is first freed from oxygen by passing nitrogen (5 minutes) then boiled for 2 hours under reflux. The reaction mixture is cooled to room temperature, filtered through infusoria soil, the filtrate is evaporated, recrystallized from ether-iso-

propanol. Indoline-2S-carboxylic acid hydrochloride is obtained,

which melts during cleavage at 133°C /Wrj= -70.4.<0>

(c = 1 in ethanol).

A solution of 34 g of the latter for-

bond is saturated without cooling with dry hydrogen chloride. The mixture is stirred for 2 hours at room temperature and the solvent is evaporated to binding crystallization. The concentrate is poured into ^00 ml of diethyl ether, cooled for 1 hour

at 0°C, and filtered. Indoline-2S-carboxylic acid ethyl ester hydrochloride is obtained which melts at 179-181°C faJ- q =

-63° (c = 1.385 in ethanol).

A mixture of 18.0 g of the latter compound, 18.5 g of N-carbobenzyloxy-S-analine, 11 ml of triethylamine and 4.00 ml of methyl chloride is mixed with stirring at 0°C with 16.7 g of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After one hour the temperature is allowed to rise to room temperature,

and continue stirring overnight. The mixture is then washed with water, 2-normal hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and evaporated. 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 3 times with 100 ml of methylene chloride each time. The combined extracts are washed with water, dried and concentrated to 50 ml. The concentrate is diluted with 300 ml of diethyl ether, extracted 3 times with each time 100 ml saturated in aqueous sodium hydrogen carbonate solution, the combined extracts are acidified with concentrated hydrochloric acid, and extracted with methylene chloride. The extract is dried and evaporated. 1-(N-Carbpbenzyloxy-S-alanyl)-indoline-2S-carboxylic acid is obtained which melts at U4-U6°C.

A mixture of 15 g of the latter compound,

1.0 g of palladium-on-charcoal catalyst and 150 ml of 90% in. g of aqueous ethanol are hydrogenated at room temperature and atmospherically.

pressure for 2 hours, filtered and evaporated. 1-(S-alanyl)-indoline-2S-carboxylic acid is obtained which melts at 205-207°C. /"a/rj - -14-1» 8° (c = 1.1 in water).

Example 2

A mixture of 0.50 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 0.66 g of 4-phenyl-2-oxobutanoic acid ethyl ester, 0.4-3 g of triethylamine, 0, 7 g of Raney nickel, 2 g of 3A molecular layer and 20 ml of ethanol are hydrogenated at room temperature, and:.2^7 atmosphere 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 with 2-normal aqueous sodium hydroxide solution to a pH value of 8.6. the aqueous phase is separated and washed with 10 ml of ethyl acetate. The aqueous phase is adjusted with 4-normal hydrochloric acid to a pH value of 4-, 25, and extracted 3 times with 10 ml of acetic acid ethyl ester each time. The combined extracts are dried and evaporated. One obtains 1 -/N-'-,(■ 1 -carbp.ethoxy-3-phenylrpopyl)-S-alanyl_7-indoline-2S-carboxylic acid, which has an IR band' at 3210 , 174-5 and 1720 cm "<1.>[ °JQ - - 103.4°'"i (c = 0.6 in ethanol).

0.5 g of the latter compound is dissolved in

5 ml of diethyl ether. introduce anhydrous hydrogen chloride into the solution. The precipitate formed is filtered off, washed with diethyl ether. 'and dried. The corresponding hydrochloride is obtained which melts at 176-180°C.

Example 3

Analogous to the methods discussed here, the following 1-(carboxy-azaralkanoyl)-indoline-2S-carboxylic acid is prepared with the formula

II:

Example 4-'

A mixture of 5.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 22.0 g of 2-oxo-4-phenylbutanoic acid ethyl ester,

6.0 ml of triethylamine and 33.0 g of 3 A-mole spherical sieve in 75 ml of ethanol are stirred at room temperature for 30 minutes. A solution of 1.34 g of sodium cyanoborohydride in 25 ml of ethanol is added over the course of 3 hours. The reaction mixture is stirred overnight at room temperature, filtered and the filtrate is evaporated to dryness. The residue is shaken with 30 ml of methylene chloride and 50 ml of water while adjusting the pH value with 2-normal aqueous sodium hydroxide solution to 9. The aqueous phase is separated and washed with 30 ml of methylene chloride.

The aqueous solution is adjusted with concentrated hydrochloric acid to pH value s1, stirred for 30 minutes, adjusted by addition of ?i2-normal sodium hydroxide solution to pH value 3, and then extracted 3 times with 50 ml of methylene chloride.

The methyl chloride extract is dried over magnesium sulfate and evaporated to dryness. A product is obtained which mainly consists of the desired diastereomer isomer. This is purified on a silica gel column by high-pressure liquid chromatography. An 85:15 mixture of acetic acid ethyl ester and methanol is used as eluent. One obtains 1-/N-(1S-carbo-etocy-3-phenyl-propyl)-S-alanyl_7-indoline-2S-carboxylic acid. This product is dissolved in diethyl ether, mixed with anhydrous hydrogen chloride, and the hydrochloride salt formed is separated.

1 -/N-(1S-carboethoxy-3-phenyl-propyl)-S-alanyly-indoline-2S-carboxylic acid hydrochloride is obtained, which melts during cleavage at U0°G. /"q7D= -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-oxo-4-phenylbutanoic acid ethyl ester, 22 g of diisopropylethylamine, 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 the course of 5 hours. The reaction mixture is further stirred for .1 hour, filtered and evaporated under reduced pressure. aqueous suspension of the residue is washed twice with 150 ml of ether. The pH value is adjusted with concentrated hydrochloric acid to T, 5, and 100 ml of methylene chloride is added. The mixture is stirred for 1 hour and the pH value is adjusted with 10% in aqueous sodium hydroxide to 2, 9. The methylene chloride layer is separated, and the aqueous phase is extracted twice more with 100 nil methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The product formed is recrystallized from 150 ml of ether. 1 -/N-( 1S-carboethoxy-3-phenyl-propyl)-S-alanyl 7-indol'ine-2S-carboxy hydrochloric acid, which melts during cleavage at 80°C. 'faJB= -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 2-oxo-4-phenylbutyric acid ethyl ester and 6 ml of triethylamine in 115 ml of ethanol is hydrogenated in the presence of 4-, 8 g Raney nickel and 17 g 3A molecular layer 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 acetic acid and 50 ml of water, adjusting the pH value with 2-normal aqueous sodium hydroxide solution to 8.6. The aqueous phase is separated, washed with 20 ml ethyl acetate,

is set with 4--normal hydrochloric acid at a pH value of 4-» 25,

and extracted 3 times with 50 ml ethyl acetate. The combined last three acetic acid ethyl ester extracts are dried over sodium sulfate and evaporated to dryness. The residue is treated with anhydrous hydrogen chloride in diethyl ether. The hydrochloride salt formed is separated and recrystallized from acetic acid ethyl ester. One obtains 1-(1R-carboethoxy-3-phenyl-propyl)-S-alanyl_7-indoline-2S-carboxylic acid hydrochloride, which melts at 207-208<G>C. [ aj^ = -109.6° (c = 1.09 in ethanol).

Example 7

A mixture of 6.4 g of sodium 3-phenyl-2-oxo-propanoate, 2.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid and 1.6 g of sodium cyanoborohydride in 50 ml of water is set at room temperature with 1-normal hydrochloric acid at a pH value of 7. The reaction mixture is stirred at room temperature for two days, and 10 ml of concentrated hydrochloric acid is added, and evaporated under reduced pressure. The product formed is absorbed on a strongly acidic ion exchange column, .("Dowex" .;;; 50 H + - form) and eluted with 4-% in aqueous ammonia. One obtains 1-/N-(1-kar bok sy-2-fe nylet yl )-S-alanyl_7-indolin-2S-kar bok syl syre ,

which melts at U0-U3°<C>[ aj^<=><->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 1-(S-alanyl)-indqlin-2S-carboxylic acid, 13 g of 3A molecular sieve, 2.4 ml of triethylamino and 5.0 g of purogravic acid ethyl ester in 30 ml of ethanol is stirred for 30 minutes at room temperature. A solution of 0.54 g of sodium cyanoborohydride in 10 ml of ethanol is added over the course of 2 hours. The reaction mixture is stirred overnight at room temperature, washed with 4 ml of concentrated hydrochloric acid and evaporated to dryness. The product formed is absorbed on a strongly acidic ion exchange column ("Dowex" 50, H+<->form), and the column is eluted with 4 µg aqueous ammonia. One obtains 1-^N-(1-carboethoxy-ethyl)-S-alanyl7-indoline-2S-carboxylic acid, which DMS0 has NMR peaks at 3.8, 1.6 and 1.2 ppm.

Example ' 9

A solution of 0.5 g of 1 -/N-(1 S -carboethoxy-3-i.'--; phenyl-propyl)-S-alanyl7-indoline-2S-carboxylic acid in 25 ml of ethanol is saturated at 0°C with ammonia, and is left in a pressure vessel for k days. The solution is then evaporated, the residue is taken up in water, the mixture is adjusted with 3-normal hydrochloric acid at 0°C to a pH value of 3.5 and extracted with methylene chloride. One obtains 1-/N-(1S-carbamoyl-3-phenyl-propyl)-S-alanyl_7_indoline-2S-carboxylic acid which in the IR spectrum has peaks at 1710, 1660 and 3'220 cm-1

Example TWO.

Production of 10,000 tablets each containing 5 mg of the active substance:

Ingredients:

Approach:

All powdered components are sieved with a sieve of 0.6 mm mesh size. The active substance is then mixed with milk sugar, talc, magnesium stearate and with half of the starch in a suitable mixer. The other half of the starch is suspended in 4-0 ml of water, and the suspension is added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powders and granulated if necessary with the addition of a further amount of water. The granulate is dried overnight at 35°C, passed through a sieve of 1.2 mm mesh size, and pressed to

tablets' with. 6, J+ > mm diameter which has a breaking drill.

Example 11

.'i .ii, Production of 10,000 tablets with a content of 10 mg each of the active substance:

Components:

Approach:

All powdered ingredients are sieved

with a sieve of 0.6' mm mesh size'. The active substance is then 'homogenised' first with talc and then with milk sugar in a suitable mixer. Capsules No. 3 are filled with 200 mg of the mixture each, using a filling machine.

In an analogous way, tablets or capsules are prepared from other compounds prepared according to the invention, e.g. such as are indicated;, in the further examples.

Example T2

A mixture of 1-(S-alanyl)-indoline-2S-carboxylic acid (100 g), 2000 ml of anhydrous ethanol, 29.9 g of acetic acid and 270 g of 4-phenyl-2-oxo-butanoic acid ethyl ester is stirred for 2 hours at room temperature. 33.3 g of sodium cyanoborohydride in 300 ml of anhydrous ethanol are then added evenly over 5 hours, keeping the temperature between 20 and 24°C. The reaction mixture is stirred overnight at room temperature, and then cooled to 0°C, mixed with 100 ml of 12-molar hydrochloric acid all at once, and the cooling interrupted. The mixture is stirred for 1 hour, and then evaporated at 3 mm

Hg, and 20-24-°C. The syrup formed is added to a vigorously stirred mixture of 600 g of ice, 600 ml of 6-normal sodium hydroxide, and 1000 ml of ether. The aqueous phase is separated and washed with 1000 ml of fresh ether. The aqueous solution (pH value approx. 1.24) is mixed with 1000 ml of methylene chloride, and cooled to 0-5°C, and quickly acidified with approx. 93 ml of 12-normal hydrochloric acid to a pH value of •4-»3 - Methylene chloride is separated, and the aqueous mixture is extracted twice with 500 ml of methylene chloride each time. The combined organic solutions are dried over anhydrous sodium sulfate, clarified by filtration and evaporated at 20-24°C, and 3 mm Hg. 1N-(fS-carboethoxy-3-phenylpropyl)-S-cyanyl-7-indoline-2S-carboxylic acid is obtained as a foam.

194 g of the formed crude base are dissolved in

500 ml acetic<y>reethyl ester, and put the solution dropwise

add to a strongly stirred solution of 4-2 g of phosphoric acid in 2300 ml of ethanol. The mixture is kept overnight at 5°C, then stirred for 1 hour, and the precipitate is filtered off. The filter cake is washed three times with each time 100 ml of acetic acid ethyl ester, and three times with each time 100 ml of ether, and dried at 24°C and 3 mm Hg. The crude phosphate salt formed is recrystallized from a mixture of absolute ethanol/acetic acid ethyl ester and dried at 24°C and 0.01 mm Hg. One obtains 1 -/N-(1S-carboethoxy-3-phenylpropyl)-S-alanyl_7-indoline-2S-carboxylic acid-1:1-phosphate, which melts at 1 25-129°C 87.2° ( c = '1 "in' methanol).

Example 13

A solution of 3.76 g of sodium hydroxide in 100 ml of ethanol is mixed at room temperature with a suspension of 16.0 g of 1-[N-(1S-carboethoxy-3-phenylpropyl)-S-alanyl_7-indoline-2S-carboxylic acid T-phosphoric acid salt in 100 ml of ethanol. The mixture is stirred for 30 minutes and then filtered. The filtrate is evaporated, the residue is dissolved in 100 ml of diethyl ether, filtered,

and set aside overnight at room temperature. The crystalline product is filtered off, washed with diethyl ether and dried in a vacuum. The sodium salt of 1-[N-('1S-carbo-ethoxy-3-phenylpropyl)-S-alanyl _7~indoline-2S-carboxylic acid is obtained with m.p. T90-T92°C. [ aj ^ = -110° (c = 0.2 in ethanol).

Example 14-

1.6 g of sodium hydroxide in 50 ml of water is 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 with concentrated hydrochloric acid to pH

value 3.. The precipitate is filtered off and recrystallized from acetic acid ethyl ester. One obtains 1-[N-(1S-carboxy-3-phenyl-propyl)-S-alan<y>17-indoline-2S-carboxylic acid, which melts at 159-160°C .[ aj^ = -70.4 (c = 0.6 in ethanol).

Example 15

A solution of 3.0 g of 1-(N-(1S-carboethoxy-3-phenyl-propyl)-S-alanyl7-indoline-2S-carboxylic acid sodium salt in

Boil 30 ml of ethanol containing 100 mg of sodium carbonate

10 hours under reflux, and then infused..Re-

the residue is taken up in 150 ml of diethyl ether and filtered. The filtrate is evaporated to a volume of 50 ml, and mixed with 50 ml of hexane. The formed precipitate is filtered off. 1-/N-(1S-carbo-methoxy-3-phenylpropyl)-S-alanyl7-indoline-2S-carboxylic acid sodium salt is obtained which melts at 1 4-0-1 4.5°C. ="123.7°.

(c = 0.8 in methanol).

Starting material for example■3/3.

A solution of 5.0 g of ihdoline-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 1 - (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture is stirred overnight at room temperature, and is then washed with 75 ml of water, 75 ml of 2-normal hydrochloric acid and 75 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer is dried over magnesium sulfate and evaporated. 1 -(N-carbobenzyloxy-L-valyl)-indolin-2,S-carboxyl acid ethyl ester is obtained.

Mix 9.3 g of 1-(N-carbobenzyloxy-L-valyl)-indoline-2S-carboxylic acid ethyl ester in 75 ml of methanol with 1.05 g of sodium hydroxide in 75 ml of water. The reaction mixture re-

stirred for 3 hours at room temperature^and evaporated there-

after. The residue is taken up in 200 ml of water and washed with 75 ml of methylene chloride. The aqueous layer is diluted with 5 ml conc. hydrochloric acid, and then extracted 3 times with each

times 75 ml methylene chloride.i The combined organic extracts are dried over sodium sulphate and evaporated. 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, 0.5 g of 10% palladium is added to a charcoal catalyst. The reaction mixture is hydrogenated at room temperature and atmospheric pressure for 3 hours and evaporated. One obtains 1-(L-valyl)-indoline-2S-carboxylic acid, which melts at 194--196°C.

/VD= -63.2°v (c = 0.9 in 50% aqueous ethanol).

Issue material ' f br^ éxample 3/ 4-

To 10.0 g indoline-2S-carboxylic acid ethyl ester, 10.7 gOi-N-t-butoxycarbonyl-e-N-benzyloxycarbonyl-L-

lysine and 6.1 ml of triethylamine in 250 ml of methylene chloride, 8.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred overnight at room temperature, washed with 75 ml of water, 75 ml of 2-Normal aqueous hydrochloric acid and 75 ml of saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated. One obtains 1 - (ot-N-t-butoxy-carbonyl-e-N-benzyloxycarbonyl-L-lysyl)-indoline-2S-carboxylic acid ethyl ester.

A solution of 22.5 g of 1-(α-N-t-butoxycarbonyl-ε-N-benzyloxycarbonyl-L-lysyl)-indoline-2S-carboxylic acid ethyl ester in 150 ml of methanol is mixed with a solution of 1.8 g of sodium hydroxide in 150 ml of water. The reaction mixture is stirred for 3 hours at room temperature 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 acidified with 5 ml conc. hydrochloric acid, and extracted 3 times with 100 ml of methylene chloride each time. The combined organic extracts are dried over magnesium sulfate and evaporated. 1-(a-N-t-butoxycarbonyl-e-N-benzyloxycarbonyl-L-lysyl)-indoline-2S-carboxylic acid is obtained.

To 7.6 g of 1-(a-N-t-butoxycarbonyl-e-N-benzyloxycarbonyl-L-lysyl)-indoline-2S-carboxylic acid-in 13 ml

glacial acetic acid, 20 ml of methylene chloride and 13 ml of anisole are placed at 0°C in 4-0 ml of trifluoroacetic acid. The reaction mixture is allowed to warm to room temperature under stirring for 30 minutes, and then evaporated. The residue recrystallized

seres from diethyl ether. The trifluoroacetic acid salt of 1-(ε-N-benzyloxycarbonyl-L-lys.yl)-indoline-2S-carboxylic acid is obtained.

Cardiovascular. pharmacology of compounds prepared according to the invention.

Examination of the effect of the compounds has been carried out according to the methods for assessing the inhibition of the enzyme that converts angiotensin (angiotensin coverting enzyme '= ACE). In the biochemical assessment of the in vitro ACE inhibition (ACE inhibition = ACEI), the activity is determined

of the compound in rabbit lung tissue.

In the in vivo test method, an increase in blood pressure is first produced* by the administration of angiotensins I (Al) to experimental animals. The inhibition of the individual compounds on this increase in blood pressure is then measured.

I. Biochemical test method.

A rabbit lung tissue preparation was used

Z~(Das and Saffer, J Biol. Chem. 250, 6762 (1975)_7 for the determination of ACE according to the method of Cheung and Cushman /Cheung and Cushman, Biochem. Biophys. Acta 293, 451 (1973)7- I

this method determines spectrophotometrically the amount of histidyl-leucine that is released from synthetic substrate in i.<;

during an incubation of 30 minutes at 37°C. The 10,^ values of the .ACE inhibition are then calculated graphically. The ICj-q value is the concentration (in mol) of the investigated compound which reduces the amount of histidyl-leucine formed in the absence of the test substance by around 50%. II. Method of inhibiting the increase in blood pressure produced by angiotensin I (Al) by intravenous administration of the test compounds (% AI inhibition).

In these investigations, as mentioned above, a catheter is introduced each time in a femoral artery and in a femoral vein of the rats.

The arterial pressure was recorded from the arterial catheter while angiotensin I (Al) and the individual test compounds were injected through the venous catheter. The inhibition of the increase in blood pressure caused by angiotensin I is shown in the table as an average value. 30 minutes after the administration of selected doses of the possible compound. Thus, such dosages are chosen so that there is b.a. the ID^q (i.v.) value can be determined.

Results:

Claims (1)

Process for the preparation of new 1-carboxy-(azaalkanoyl or azaaralkanoyl)-indoline-2-carboxylic acids of the general formula I wherein Ph means unsubstituted 1,2-phenylene or 1,2-phenylene, substituted with one to three, the same or different substituents from the group of lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogen or trifluoromethyl, R.| means hydrogen, lower alkyl or amine--lower alkyl, Rg means lower alkyl or HPh-lower alkyl, and each of the symbols R^> R^ and R^ means hydrogen or lower alkyl, as well as their amides, mono- or dilower alkyl amides, lower alkyl esters, (amino, mono- or dilower alkylamino, carboxy or carbolower alkyl)-lower alkyl esters and their salts, characterized by 1) a Schiff's base of the general formula III or its mentioned functional derivatives, in which one of the symbols p and q means 0, and the other 1, is hydrogenated, or.2) a compound of the general formula IV or their mentioned functional derivatives, is condensed with a reactive functional derivative of a compound, with the general formula V wherein Å means hydrogen and 1 means the group HOCO-CHR^ -N-C00RQ , wherein RQ means t-butyl or benzyl, or X means CO-CHR^ -Z and one of the symbols Y and Z means amino, and the other a reactive esterified hydroxy group, and the aforementioned C00RQ group is converted to hydrogen, or3) a compound of the general formula VI in which at least one of the symbols V and W means cyan, and the other means the said free amidated or esterified carboxy group, is hydrolyzed or alcoholized or 4-) in -a connection with the general formula VII or its mentioned functional derivatives, the indole part is hydrogenated to the indole part, and if desired, a formed compound is converted into another compound according to the invention and/or if desired, the formed free compound is transferred to a salt or another salt to the free compound,! or to another salt, and/or if desired, a formed mixture of isomers or racemates is divided into the individual isomers or racemates and/or if desired, racemates formed are split into the optical antipodes.