MXPA98009376A - Derivatives benzazepinone-n-acetic, replaced phosphonic connects, asicomo procedures for preparation and medicines containing these compounds - Google Patents

Abstract

Compounds which act by inhibiting NEP are described, of the general formula I, wherein R 1 signifies hydrogen or a group forming a biolabile phosphonic acid ester, R 2 signifies hydrogen or a group forming a biolabile phosphonic acid ester, and R 3 signifies hydrogen or a group forming a biolabile carboxylic acid ester, and physiologically compatible salts of formula I acids, as well as medicaments containing these compounds

Description

Derivatives of benzazepinone-N-acetic acid, substituted with phosphonic acids, as well as procedures for their preparation and medicinal products containing these compounds The present invention relates to novel benzazepinone-N-acetic acid derivatives, which are substituted in the 3-position with a cyclopentylcarbonylamino radical carrying a methylphosphonic acid radical in position 1, and its biolabile salts and esters as well as pharmaceutical preparations containing these compounds and processes for the preparation of these compounds. From the European Patent Application, with the publication number 0.733.642, there are known derivatives of benzazepine-, benzoxazepine- and benzodiazepine-N-acetic acids, which exert an inhibitory effect on the neutral endopeptidase (= NEP). , of neutrale Endopeptidase). It is the mission of the invention to develop new pharmaceutical active substances that act by inhibiting NEP, with an effect profile that is favorable for the treatment of heart failure and blood hypertension. It has now been discovered that the novel benzazepinone-N-acetic acid derivatives according to the invention, which in the 3-position of the benzazepinone framework are substituted with a cyclopentylcarbonylamine radical carrying a methylphosphonic acid radical in position 1, possess valuable active pharmacological properties on the heart, and are distinguished by a profile of effects that is favorable for the treatment of cardiovascular diseases, especially heart failure, whose profile is characterized by a combination of a pronounced inhibitory effect on the neutral endopeptidase together with an inhibitory effect on the endothelin converting enzyme (=? CE, from Endothelin Convertipg Enzyme), and of good compatibility.

The subject of the invention are novel compounds of the general Formula I wherein RJ means hydrogen or a group forming a biolabile phosphonic acid ester, R 2 signifies hydrogen or a group forming a biolabile phosphonic acid ester, and R means hydrogen or a group forming a biolabile carboxylic acid ester, and physiologically compatible salts of the acids of Formula I, as well as processes for the preparation of these compounds and medicaments containing these compounds. The compounds of Formula I constitute acid derivatives containing carboxylic acid and phosphonic acid groups, optionally esterified by groups forming biollabile esters. The biolabile esters of Formula I constitute prodrugs of free acids. Depending on the form of application, biolábile esters or acids are preferred, the latter being suitable especially for intravenous application. (go . ) . As groups R1 and R ^ which form phosphonic acid biolabile esters, the groups which, under physiological conditions, can be separated in vivo, by releasing the respective function of phosphoric acid, are suitable. For example, lower alkyl groups, C2-Cg-oxymethyl alkanoyl groups optionally substituted by lower alkyl in the oxymethyl group, or phenyl or phenyl-lower alkyl groups, whose phenyl ring is optionally substituted once or multiple times, are suitable for this purpose. with lower alkyl, lower alkoxy or with a lower alkylene chain attached to two adjacent carbon atoms. If the group R1 and / or R2 which forms a biolabile ester means or contains lower alkyl, it may be branched or unbranched and contain from 1 to 4 carbon atoms. If R1 and / or R2 represent an optionally substituted alkanoyloxy ethyl group, it may contain a preferably branched alkanoyloxy group, with 2 to 6, preferably 3 to 5 carbon atoms, and may represent, for example, a pivaloyloxymethyl radical (= tere.-butylcarbonyl) -xymethyl). If R1 and / or R2 represent a phenyl-lower alkyl group optionally substituted, this may contain an alkylene chain with 1 to 3, preferably 1, carbon atom (s). If the phenyl ring is substituted with a lower alkylene chain, it may contain from 3 to 4, especially 3, carbon atoms, and the substituted phenyl ring represents especially indanyl. As groups R3 which form esters of biolabile carboxylic acids, groups which under physiological conditions can be separated in vivo, by eliminating the carboxylic acid are appropriate. For example, lower alkyl groups, phenyl or phenyl lower alkyl groups optionally substituted on the phenyl ring once or several times with lower alkyl or lower alkoxy or with a lower alkylene chain attached to two adjacent carbon atoms are suitable for this purpose. dioxolanylmethyl groups optionally substituted on the dioxolane ring with lower alkyl, or C2-g-oxymethyl alkanoyl groups optionally substituted on the oxymethyl group with lower alkyl. If the group R3 which forms a biolabile ester means or contains lower alkyl, it may be branched or unbranched and contain from 1 to 4 carbon atoms. If the group forming a biolabile ester represents a phenyl-optionally substituted lower alkyl group, it may contain an alkylene chain with 1 to 3, preferably 1, carbon atom (s) and preferably represents benzyl. If the phenyl ring is substituted with a lower alkylene chain, it may contain from 3 to 4, preferably 3, carbon atoms. If R3 represents an optionally substituted alkanoyloxymethyl group, it may contain an alkanoyloxy group preferably branched with 2 to 6, preferably 3 to 5, carbon atoms, and may for example represent a pivaloyloxymethyl radical. According to the invention, the novel compounds of Formula I and their salts are obtained, in a manner known per se for the preparation of compounds of general Formula IV wherein R101 and R201 mean, in each case independently of one another, hydrogen or a phosphonic acid protecting group and R302 means a carboxylic acid protecting group, by reacting compounds of the general Formula II wherein R1x0? 1 and r90U1i possess the above meanings, with compounds of general Formula III in which RJU ,? has the above meaning, and, in the case that R101 and / or R201 mean hydrogen, by transforming the free phosphonic acid (s) (s) function (s) as desired by esterification with a compound of the general formulas Va and / or Vb wherein R 11 p and R i p each mean a group forming a biolabile phosphonic acid ester and Y means hydroxy or a separable labile group, in a biolabil phosphonic acid ester group, and if in the compounds of Formula IV the protecting groups R10, R201 and / or R302 do not represent any of the desired groups forming biollabile esters, separating these groups simultaneously or individually, one after the other, in any order of succession and if desired transforming the functions of acids which in each case are released into groups of biollabile esters, esterifying functions of free phosphonic acids with a compound of Formula Va or Vb and / or esterifying the function of free carboxylic acid with a compound of the general formula Go R310_? (Go) wherein R310 means a group that forms esters of biolabile carboxylic acids and Y has the above meaning, and if desired transforming acids of the Formula I into their physiologically compatible salts or transforming salts of the acids of the Formula I into the free compounds.

As physiologically compatible salts of acids of the formula I, their salts of alkali metals, alkaline earth metals or ammonium, for example their sodium, potassium or calcium salts, or salts with pharmacologically neutral and physiologically compatible organic amines are in question in each case , such as, for example, diethylamine, tere. -butylamine or phenyl-lower alkyl-amines such as a-methyl-benzyl-amine. As protecting groups R101 and R201 of phosphonic acids s = can choose the usual protective groups for the protection of phosphonic acid functions, which are then separated again according to methods known per se. As protective carboxylic acid groups R302, customary protecting groups can be selected for the protection of carboxylic acid functions, which can then be separated again according to methods known per se. Suitable protecting groups for carboxylic acids are known, for example, from McOmie's "Protective Groups in Organic Chemistry", Plen m Press and Green, Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience Publication. Suitable protective groups for phosphonic acids are known from the work of Houben, Weyl "Methoden der Organischen Cherr.te", G. Thieme Verlag Stuttgart, New York 1982, pages 313-341, as well as the works of M Kluba, A. Zwierak "Synthesis" 1978, pages 134-137 and from McOmie, "Protective Groups in Organic Chemistry", Plenum Press. As acid protecting groups, groups which form a biolabile ester can also be used. The compounds of Formula IV, obtained by reacting compounds of Formula II with compounds of Formula III, already constitute in these cases esters of Formula I according to the invention. According to the invention, as protecting groups R101 and R201 of phosphonic acids, groups which can be selectively separated or selectively introduced according to appropriate methods, independently of one another and independently of a protecting group R302 of carboxylic acid which optionally is still available, are suitable. present in the molecule. As a general rule, the phosphonic acid protecting groups can be easily separated by trimethylsilyl bromide., in the presence of protective groups of carboxylic acids. As examples of protecting groups of phosphonic acids, which can be separated under various conditions, which can also form groups forming phosphate-forming esters of biolabile acids, will be mentioned below: Unbranched lower alkyl groups such as ethyl, which can be easily separated, for example, by such acids as trifluoroacetic acid, verifying that, if both functions of phosphonic acids are esterified with unbranched lower alkyl groups, under basic conditions only one of these alkyl groups can be separated. Lower branched alkyl groups, such as tere. -butyl, which under acidic conditions, for example lower the action of trifluoroacetic acid, can be easily separated. Phenylmethyl groups optionally substituted on the phenyl ring, such as benzyl, which can be easily separated by hydrogenolysis. Acycloxymethyl groups such as pivayloyloxymethyl, which can be easily separated, for example, by acids such as trifluoroacetic acid. Phenylmethyl groups substituted ur.a or multiple times with lower akoxy in the phenyl ring, such as p-methoxybenzyl, which can be separated relatively easily under oxidizing conditions, for example under the action of 2,3-dichloro-5, 6-dicyan-l, 4-benzoquinone (= DDQ) or cerium-ammonium nitrite (= CAN). As groups R302 protective of carboxylic acids are suitable groups that can be selectively separated or selectively introduced, independently of the protecting groups of phosphonic acids that for example are still present in the molecule. As examples of protecting groups of carboxylic acids separable under various conditions, which may also constitute groups forming stapes of biolabile carboxylic acids, there will be mentioned: Unbranched lower alkyl groups such as ethyl, which can be separated relatively easily under basic conditions. Branched lower alkyl groups such as tere. -butyl, which can be easily separated by acids such as trifluoroacetic acid. Phenylmethyl groups optionally substituted on the phenyl ring, such as benzyl, which can be easily separated by hydrogenolysis or also under basic conditions. Phenylmethyl groups substituted once or multiple times with lower alkoxy on the phenyl ring, such as p-methoxybenzyl, which can be separated relatively easily under oxidizing conditions, for example under the action of DDQ or CAN. The compounds of Formula I contain a chiral carbon atom, namely the carbon atom bearing the amide side chain, located in position 3 of the benzazepine framework. The compounds can therefore be present in two optically active stereoisomeric forms or as a racemate. The present invention encompasses both racemic mixtures as well as compounds of Formula I that are pure in the isomers. If in compounds of Formula I R1 and R2 do not represent hydrogen and have respectively different meanings, the phosphorus atom of the phosphonic acid group can also be chiral. Also subject to the invention are mixtures of isomers that are formed by chiral phosphorus atoms, and compounds of Formula I that are pure in terms of isomers.

The reaction of the acids of the formula II with the amines of the formula III to form the amides of the formula IV can be carried out according to customary methods for the formation of amino groups by aminoacylation. As acylating agents, the carboxylic acids of Formula II or their derivatives capable of reacting can be used. Derivatives capable of reacting are especially anhydrides of mixed acids or acid halides. Thus, for example, chlorides or bromides of the acids of the formula II or mixed esters of the acids of the formula II can be used with organic sulphonic acids, for example with lower alkane sulphonic acids optionally substituted with halogen, such as methanesulfonic acid or trifluoromethanesulfonic acid, or with aromatic sulfonic acids, such as p. ex. benzenesulfonic acids, or with benzenesulfonic acids substituted with lower alkyl or halogen, p. ex. toluenesulphonic acids or bromobenzenesulfonic acids. The acylation can be carried out in an organic solvent that is inert under the reaction conditions, at temperatures between -20 ° C and room temperature. Suitable solvents are halogenated hydrocarbons, such as diclcromethane, or aromatic hydrocarbons, such as benzene or toluene, or cyclic ethers, such as tetrahydrofuran (= THF) or dioxane, or mixtures of these solvents. The acylation can be carried out conveniently, especially when, as the acylating agent, a mixed anhydride of the acids of the formula II is used with a sulphonic acid, in the presence of an acid-binding reagent. Suitable acid-binding agents are, for example, organic bases soluble in the reaction mixture, such as tertiary nitrogen bases, for example tere. - lower alkyl-amines and pyridines, such as p. ex. triethiamine, triprcpilamine, N-methyl-morpholine, pyridine, 4-dimethylamino-pyridine, 4-diethylamino-pyridine or 4-pyrrclidino-pyridine. The organic acids used in excess can also serve as solvents at the same time. In the case that the acids of Formula II themselves are used as acylating agents, the reaction of the amino compounds of Formula III with the carboxylic acids of Formula II can be conveniently carried out also in the presence of a reagent of known coupling of peptide chemistry as appropriate for the formation of amides. As examples of coupling reagents, which favor the formation of amines with the free acids, in such a way that they react with the acid itself, with the formation of an acid derivative capable of reacting, especially mention will be made of: Alkyl-carbodiimides, p . ex. cycloalkyl carbodiimides, such as dicyclohexylcarbodiimide or N- (3-dimethylamino-propyl) -N'-ethylcarbodiimide, carbonyl-diimidazole and salts of N-lower alkyl-2-halogen-pyridinium, especially halides or toluenesulfonates. The reaction in the presence of a coupling reagent can be conveniently carried out at temperatures of -30 ° to + 50 ° C in solvents such as halogenated hydrocarbons and / or aromatic solvents and optionally in the presence of an acid-binding amine, which has been described above. From the compounds of Formula IV, obtained by reaction of the compounds of Formula II with the compounds of Formula III, the protective groups R 101 R '201, 302 provided that they do not represent any of the desired groups that form biollabile esters, they can be separated in a manner known per se. If compounds of the formula I are to be prepared, in which R, R2 and R3 represent identical groups that form a bioavalent ester, identical protecting groups are conveniently chosen in the starting compounds of the formula II and in the starting compounds of Formula III. Conveniently, protective groups can be chosen in this case, which simultaneously constitute groups to form, biolabile esters. If free acids of the Formula I are to be prepared, in which R, R2 and R3 represent in each case hydrogen, they can be chosen as protecting groups R, 1i0U1-, and groups separable in each case under the same conditions, preferably under hydrogenic conditions. For example, they can be chosen for R 101 R201 and R302 in each case benzyl groups, which are separated under the conditions of a catalytic hydrogenation simultaneously to form the free acid groups. Catalysts for catalytic hydrogenation can be used, for example, noble metal catalysts such as palladium on active carbon. The reaction can be carried out in a solvent which is inert under the conditions of the reaction, for example a lower alcohol such as ethanol or a lower alkyl ester such as ethyl acetate, or in mixtures of these solvents . Conveniently, the catalytic hydrogenation is carried out at a hydrogen pressure of 2 to 6 bar and at room temperature. If groups of free phosphonic acids and / or free carboxylic acid groups of compounds of the formula I are to be esterified, groups of free phosphonic acids of compounds of the formula I with compounds can be reacted in a manner known per se. of the Formula Va or Vb. The free carboxylic acid groups of compounds of the formula I can be reacted in a manner known per se with compounds of the formula Ve. As halogen groups and in compounds of the formulas Va, Vb and Ve, halogen, especially chlorine, is suitable. or bromine, or lower alkane sulphonic acid radicals such as for example trifluoromethanesulfonyloxy, or aromatic sulfonic acids such as those of benzenesulfonic acids, or of benzenesulfonic acids substituted with lower alkyl or halogen, such as toluenesulfonic acids. If compounds of the formula I are to be prepared, in which y have in each case the same meaning, but different from R, it is conveniently starting from starting compounds of the formula II, in which R101 and R201 have identical meanings, and of starting compounds of the Formula III, in which R 302 has a different meaning from those of R101 and R20. For example, you can choose groups R101 and R201 phosphonic acid protectants, which are stable under hydrogenolytic conditions, such as lower alkyl, preferably ethyl. Simultaneously, a group removable under hydrogenolytic conditions, such as the benzyl group, can be used as the carboxyl group protecting group R302. Under the conditions of a catalytic hydrogenation, only the benzyl group R302 is separated in the obtained compounds of the Formula IV to form the free carboxylic acid, while the ethyl groups R101 and R201 are retained. If desired, the free carboxylic acid can then be esterified with a compound of the formula Ve. Likewise, in compounds of the formula I, in which the phosphonic acid protecting groups R101 and R201 mean groups stable under hydrogenolytic conditions, such as lower alkyl group, preferably ethyl, and R302 represents a group removable by hydrogenolysis, such as the benzyl group, first the ethyl groups R101 and R20 are separated under acidic conditions, the benzyl group R30 being preserved. If desired, the free phosphonic acid groups can then be esterified with compounds of the formula Va or Vb, for example with pivaloylcycmethyl chloride. Subsequently, the benzyl group J09, separable under hydrogenolytic conditions, can be separated under conditions known per se by catalytic reduction with hydrogen, in order to obtain compounds of the formula I, in which R 3 signifies hydrogen. If compounds of the formula I are desired, in which R1 and R have different signifiers, it is conveniently possible to start with starting compounds of the formula II, in which R101 and R201 have different meanings. For example, the starting compounds FForormmuullaa IIII can be chosen as starting compounds., wherein R101 means hydrogen and R201 represents a stable phosphonic acid protecting group under hydrogenolytic conditions. For example, R 901 may represent lower alkyl, preferably ethyl. If desired, the compounds obtained of the Formula I, in which R101 represents hydrogen, can then be reacted with suitable compounds of the Formula Va, in order to obtain compounds of the Formula I, in which R 1 and R 2 represent different groups that form biolábile esters. The starting compounds of Formula II, in which R101 means hydrogen, can be obtained, for example, from compounds of Formula II, in which R represents a separable group under hydrogenolytic conditions, such as benzyl, by catalytic hydrogenation in conditions known per se. In the reactions described above, the chiral carbon atoms in the starting compounds of Formula III are not modified, so that, depending on the type of the starting compounds, pure compounds can be obtained with respect to the isomers of the Formula I or mixtures of isomers. For the preparation of stereochemically uniform compounds of Formula I, stereochemically uniform compounds of Formula II are conveniently reacted with stereochemically uniform compounds of Formula III. In the case that a compound of Formula II, which does not contain any chiral phosphorus atom, is reacted with a racemic compound of Formula III, a mixture of two enantiomers of the compound of Formula I is obtained. The mixture of enantiomers can be separated, if desired, in a manner known per se, for example by separation by chromatography in the presence of chiral separation materials or by reaction of a free carboxylic acid of Formula I with appropriate optically active bases, for example ( -; - methyl-benzylamine, and subsequent separation of the optical antipodes by fractional crystallization of the obtained salts.

The starting compounds of Formula II can be obtained according to methods known per se. Thus, compounds of the formula II can be obtained, for example, by reacting compounds of the general formula VI, wherein R, 10u2¿ and in each case represent protecting groups of phosphonic acids and Y has the above meaning, with the cyclopentanecarboxylic acid of Formula VII and if desired, the protective groups R102 and / or R202 can be separated again in a manner known per se. For example, compounds of Formula VI may be used, wherein Y represents the radical of a lower alkanesulfonic acid, preferably trifluoromethanesulfonyloxy. The reaction can be carried out in a manner known per se under the conditions of a nucleophilic substitution in an organic solvent which is inert under the reaction conditions, by reaction of the cyclicpentane-carbcxylic acid with a strong base, capacitated for the formation of the dianion of the cyclopentanecarboxylic acid and subsequent reaction with the phosphonic acid ester derivative of Formula VI. Suitable solvents are, for example, dialkyl open chain ethers, such as diethyl ether, cyclic ethers, such as THF. As strong bases, for example, non-nucleophilic organic alkali metal amides, such as lithium diisopropylamide (= LDA), are suitable. Suitably, the cyclopentanecarboxylic acid is reacted in THF with two equivalents of LDA and the reaction mixture is subsequently further reacted with a compound of Formula VI. The reaction temperature can be between -70 ° and 0 ° C. The compounds of formula VI can be obtained in a manner known per se, for example by reacting the diesters of phosphonic acids of general formula VIII wherein R102 and R202 possess the above meanings, with a source of formaldehyde, for example with paraformaldehyde.

Conveniently, the reaction can be carried out without solvents and with the participation of soluble bases in the reaction mixture. As bases, the non-nucleophilic bases described above can be used for the reaction of compounds of Formula II with compounds of Formula III. Conveniently, the reaction can be carried out at temperatures between 50 and 130 ° C, preferably between 80 and 120 ° C. If desired, the compounds obtained from Formula VI, in which Y means hydroxy, can be transformed below in a manner known per se in compounds of Formula VI, in which Y represents a separable leaving group The compounds of formula VIII are known or can be prepared according to known procedures. phosphonic acids of Formula VIII, esterified with two different biolabile groups, separating from the diesters of phosphonic acids of the general Formula VIII, in which R101 and R? 90U1J- mean in each case the same group, for example lower alkyl, mediating the action of a base such as an alkali metal hydroxide, for example sodium hydroxide, firstly one of the two ester groups, and reacting the obtained monoester, or one of its salts, subsequently with a corresponding compound of the Formula Va or Vb. For the acceleration of the reaction, appropriate catalysts such as tetra-lower alkyl ammonium salts, for example tetrabutylammonium hydroxide, can be added. Suitably, suitable alkali metal halides such as alkali metal iodides, for example sodium iodide, can be added to the reaction mixture in order to accelerate the course of the reaction. The reaction can be carried out in a dipolar aprotic solvent such as a lower alkyl cyanide, for example acetonitrile, a lower aliphatic ether such as diethyl ether, THF or dioxane, in dimethylformamide (= DMF), in dimethylsulfoxide (= DMSO) or in mixtures of these solvents. The appropriate temperatures for this are located between 0 ° C and 80 ° C, preferably between 5GC and 40 ° C. The compounds of Formula III are known from the European Patent Application with the publication number 0.733.642 and can be prepared according to the methods described therein. The compounds of Formula I and their pharmacologically acceptable salts are distinguished by interesting pharmacological properties. In particular, the substances inhibit the endothelin converting enzyme (ECE) and the neutral endopeptidase (NEP) and therefore have an effect profile, which is especially favorable for the treatment of heart failure. In the case of heart failure is reached, by a performance of ejection of the heart that has been reduced due to a disease, to a peripheral vascular resistance reflexively increased. With it, the cardiac muscle (myocardium) must pump against an increased persistent load. This leads, in a devilish circuit, to an increased effort for the heart and further worsens the situation. The increase in peripheral resistance is mediated, inter alia, by the vasoactive peptide endothelin. Endothelin is the strongest vasoconstrictive substance in the body that is currently known, and is formed from the Big Endothelin precursor through the cooperation of the ECE enzyme. In the symptomatology of heart failure, due to the decreased performance of cardiac ejection and the increase in peripheral resistance, there is a phenomenon of stagnation of blood in the pulmonary circulation and in the heart itself. This leads to an increased tension on the walls of the myocardium in the area of the atria and ventricles. In such a situation, the heart functions as an endocrine organ and secretes, among others, the peptide ANP 'atrial natriuretic peptide = Atriales Natriuretisches Peptid) to the blood circulation. Through its pronounced vasodilator and natriuretic / diuretic activity, the ANP produces both a reduction in peripheral resistance and also a decrease in circulating blood volume. The consequence is a pronounced decrease in the previous load and the persistent load. This constitutes an endogenous cardioprotective mechanism. This endogenous positive mechanism is limited by the fact that the ANP has only a very short half-life value in the plasma. The reason for this is that the hormone is degraded very quickly by NEP. The compounds according to the invention, by means of an inhibition of the activity of the CS, prevent the formation of endothelin and in this way counteract an increase in the peripheral resistance, which consequently leads to a relief for the myocardium. The substances according to the invention also lead, by means of an inhibition of the NEP activity, to higher levels of ANP and to a prolonged duration of the effect of the ANP. This leads to a reinforcement of the endogenous cardioprotective mechanism mediated by the ANP. Especially, the substances have a high effectiveness with respect to a reinforcement of the diuretic / natriuretic activities induced by the ANP. NEP participates not only in the degradation of ANP but also in the degradation of endothelin. It follows that a pure inhibition of the NEP together with the desired increase in the level of ANP would also lead to an unfavorable increase in the level of endothelin. For this reason, a mixed profile of inhibition of ECE and NEP should be considered as especially favorable, since this, in turn, inhibits the degradation of the ANP that acts in a natriuretic / diuretic manner (blockade of the NEP) and also simultaneously inhibits the formation of endothelin (inhibition of ECE). With this, the negative concomitant effect of pure NEP inhibitors (increased endothelin level) is no longer suffered. 1. Determination of the minimum toxic dose Groups in each case of 10 rats with a body weight of 250 g (age 5 to 6 weeks) are administered maximum doses i. v. of 215 mg / kg of the test substances (dissolved in a 0.1 N aqueous solution of NaOH that had been adjusted to a pH value of 7.1 by the addition of HCl).

The animals are observed, from the time of application for 5 hours, carefully as to signs of toxicity that can be recognized clinically. In addition, they are observed twice a day until a week has passed. After this week has elapsed, each individual animal is completely dissected and all the organs are investigated on a macroscopic scale. When death or strong toxic symptoms are observed, lower doses are administered to other rats, until no more toxic symptoms appear. The lowest dose, which causes death or strong toxic symptoms, is determined as the minimum toxic dose. The test substance of Preparation Example 2 showed no significant sign of toxicity at the dose of 215 mg / kg via i. v. 2. In vitro research of the inhibitory effect of NEP presented by substances For the detection of the inhibitory effect of the substances according to the invention on the neutral endopeptidase (= NEP), in a standardized test, the inhibitory effect of the substances on the hydrolytic degradation of methionine-enkephalin (= Met. enkephalin) that occurs because of the enzymatic action of NEP. In this case, its CI5Q value was determined as a measure of the inhibitory activity of the substances. The IC50 value of a test substance that acts by inhibiting enzymes is that concentration of the test substance, with which 50% of the enzymatic activity of NEP is blocked.

Conducting the tests To carry out the tests, 100 μl of samples of different incubation solutions containing 10 ng of purified NEP (EC 3.4.24.11) and in each case different amounts of test substance as well as 20 μM of the substrate were prepared in each case. (Met-encefaliña) and 50 mM Tris buffer (= tris (hydroxymethyl) aminomethane / HCl, pH 7.4). For each test substance, 6 different incubation solutions were prepared with 3 different concentrations of the test substance, in each case as double determinations. In each test, two types of control incubation solutions are treated simultaneously in each case, on the one hand enzyme cores, which do not contain any test substance, and on the other hand cores with substrate, which contain neither enzyme nor test substance . The incubation solutions are incubated for 30 minutes at 37 ° C in a water bath subjected to shaking.

In this case the reaction with the enzyme is started after 15 minutes by the addition of the substrate (Met-encephain) and stopped at the end of the incubation time by heating at 95 ° C for 5 minutes. The arrested incubation solution is then centrifuged at 12,000 x g for 3 minutes and the concentrations of the unreacted substrate and hydrolysis products formed by the enzymatic reaction are determined in the supernatant. For this, in each case samples of the supernatant materials were separated by high pressure liquid chromatography (= HPLC) in the presence of a hydrofuged silica gel, and the products of the enzymatic reaction and the unreacted substrate are determined photometrically with a wavelength of 205 nm. For the separation of HPLC, a separation column (4.6 x 125 mm) is used which, as a reversed phase separation material, contains Nucleosin® C 18, 5 μ. The flow rate of solvent is 1.0 ml / min, the column is heated to 40 ° C. The eluent A is 5 mM H3P04, pH 2.5, and the eluent B is acetonitrile + 1% 5 mM H3PO4, pH 2.5. From the concentrations of hydrolysis products and the unreacted substrate, which are measured in the different samples, the IC.sub.Q value is calculated for the test substances in a manner known per se. The test substance of Preparation Example 2 showed in this test a CI ^ Q value for the inhibition of NEP of 1.7 nM and thus manifested as a very potent inhibitor of NEP. 3. In vivo determination of the influence of substances on diurßsis / natriurßsis in rats loaded with volume The in vivo activity was investigated in a rat charged with volume. In this experiment, an infusion of isotonic sodium chloride solution results in a high cardiac filling pressure, as a result of which a release of ANP and consequently a diuresis / natriuresis is achieved.

Conducting the tests The experiments are carried out with male Wistar rats having a body weight of 200-400 g. Through neuroleptic analgesia (fentanyl, Hypnorm®, manufacturer entity Janssen), a catheter is attached to the right femoral vein for the background infusion and volumetric loading with an isotonic solution of sodium chloride. After having opened the abdominal cavity, a second catheter is inserted into the vein and the urinary ducts are ligated, so that a measurement of urine volume, natriuresis and kaliuresis is possible. The abdominal space is closed again and the animals receive a permanent infusion with a solution of sodium chloride (0.5 ml / 100 g of body weight) during the entire period of time of the experiment, of 2 hours. After a 30-minute equilibration period, urine samples are collected in a precursor phase before the addition of test substance, three times in each case for a period of 10 minutes. These precursor values ("pre-drug" values) are determined in order to verify that a continuous flow of urine occurs in the animals under test. Then, the solutions containing the test substances are administered intravenously (injection of boluses into the femoral vein) or orally (via esophageal tube) into groups of 10 rats each. For both forms of application, in each case a group of control animals receive only placebo solutions, which do not contain any active substance. At 5 minutes after the application i. v. or at 120 minutes after oral administration of the substances, the rats are loaded i. v. with an increased volume of sodium chloride solution (2 ml / 100 g of body weight in 2 minutes) and the urine is collected for a period of 60 min. Determine the amounts of urine that result in this period of time and measure the contents of sodium and potassium contained therein. From the resulting amounts of urine the increase in the segregation that has been made under the loading with volume is interpreted, in comparison with the precursor values. The following Table 1 shows the increases in urine segregation in%, which have appeared under load with volume after administration of the test substance, referring to the segregation of urine that has been carried out under load with volume after administration of the placebo. In addition, the amounts of sodium and potassium secreted under load with volume after administration of the test substance in% of the amounts of sodium and potassium secreted under volume loading after administration of the placebo are also indicated. The numbers of Examples in Tables 1 and 2 refer to the following Preparation Examples.

Table 1 4. Investigations in vivo of the inhibitory effect of the ECE that the substances present in rats For the detection of the inhibitory effect of the substances according to the invention on the endothelin converting enzyme (= ECE), the inhibitory effect of the substances on the hydrolytic degradation of Big-endothelin (Big) was investigated in a normalized in vivo test. -ET) to form endothelin (= ET) that takes place because of the enzymatic activity of ECE. ET is a substance of the body that acts strongly vasoconstrictor. A. Increased ET level leads to an increase in blood pressure. In the case of infusion of Big-ET, an increase in blood pressure is made as ET is formed from it, by means of dissociation catalyzed by ECE. As a measure of the inhibitory effect of ECE that the substances presented, their inhibitory effect on the blood pressure increase induced by Big-ET infusion was determined.

Conducting the tests The experiments were carried out with male CD® rats of the Charles River iga entity with a body weight of 220-280 g. Mediating narcosis with ketamine / xylazine, a catheter is attached to the animals for the application of substances in the left jugular vein and a second catheter for the measurement of blood pressure in the left carotid artery. After a recovery time of 30 minutes, the animals are administered the test substance in the form of a solution intravenously (= i.v.) or intraduodenally (= i.d.). After the application of the test substances, the animals receive intravenously in each case Big-ET in a dosage of 0.5 nmol / kg. The period of time that elapses between the application of the test substance and the administration of Big-ET is, in the case of applications i. v. , every 5 minutes, in the case of the application i. d. of the test substances of Examples No. 18 and No. 22, each time of 15 minutes, and in the case of the application i. d. of the test substances of Examples N ° 8 and N ° 20, each time of 30 minutes. During the next 30 minutes, the systolic and diastolic pressures of the blood are recorded every 5 minutes. In the case of untreated animals, the infusion of 0.5 nmol / kg Big-thelin leads reproducibly to a drastic increase in blood pressure, which persists for approximately 30 minutes. The maximum of the blood pressure increase has been reached after approximately 5 minutes. The following Table 2 indicates the maximum increase in blood pressure after application of Big-ET in the case of control animals treated with a placebo solution and in the case of animals that had previously been treated in different dosages with the solutions of test substances.

Table 2 The preceding test results show that the compounds of Formula I possess high affinities for ECE and NEP and counteract in a dose-depnt manner, by inhibition of the ECE activity, the formation of ET and an increase, induced for it, peripheral vascular resistance and blood pressure. The results of the tests also show that the substances also contribute, by inhibiting the ANP degrading enzyme (NEP), to an increase in the level of ANP in blood and thereby increase the diuretic / natriuretic effects caused by the ANP, without causing an essential loss of potassium. Because of their effect described above, the compounds of Formula I are suitable as medicaments for higher mammals, especially humans, for the treatment of heart failure and for the activation of diuresis / natriuresis, especially in the case of patients who suffer from heart failure In this case, the compounds of Formula I and their biolabile salts and esters are conveniently brought into orally applicable medicinal forms. The doses to be used may be individually different and vary, of course, depng on the type of condition to be treated, the substance used and the manner of application. In general, however, for medicinal products with an active substance content of 1 to 200 mg per individual dose, suitable for higher mammals, especially humans, are suitable. As medicaments, the compounds of Formula I can be contained together with customary pharmaceutical auxiliaries in galenic preparations, such as p. ex. tablets, capsules, suppositories and / or solutions. These galenic preparations can be produced according to methods known per se by using conventional solid or liquid carrier materials, such as p. ex. lactose, starch or talc or liquid paraffins and / or by using conventional pharmaceutical adjuvants, for example tablet disintegrating agents, solubilizers or preservatives. The following Examples should explain the invention in greater detail, but should not limit its extension in any way. The structures of the new compounds were confirmed by spectroscopic investigations, especially by analyzing the IR spectra and eventually determining the optical rotating powers.

Example 1: Benzyl ester of (3S) -3- (1-dibenzyl-phosphonomethyl-cyclopentane-1-carbonyl-amino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1 acid benzyl ester -acetic A) While stirring, 100 ml of dibenzyl phosphite, 12.5 g of paraformaldehyde and 6.2 ml of triethylamine were combined. With slow heating at 55 ° C an increase in temperature was made up to 120 ° C. The now clear solution was allowed to cool to 90 ° C and was still stirred for 30 minutes at this temperature. After cooling to room temperature, it was chromatographed in the presence of 1 kg of silica gel under high pressure (eluent: mixture of n-hexane and ethyl acetate 1: 4). After concentrating the fractions and drying the residue for 12 hours under vacuum at 60 ° C, 96.1 g of oily and pure dibenzyl hydroxymethyl phosphonate were obtained, which was reacted further without further purification.

B) 17.8 g of dibenzyl hydroxymethyl phosphonate were dissolved in 120 ml of dry dichloromethane. After cooling to -50 ° C, 7.3 g of 2,6-lutidine and then 10.6 ml of trifluoromethanesulfonic acid anhydride were added dropwise, with the exclusion of moisture, consecutively. The reaction mixture was stirred first for one hour at -50 ° C, and thereafter for 1 hour at 0 ° C. For the treatment, this mixture was poured into ice-cooled water and the organic phase was washed first with diluted hydrochloric acid cooled by ice and then with ice-cooled water. After drying the organic phase over sodium sulphate and filtering it, it was concentrated by evaporation in a vacuum. The crude product obtained was chromatographed on the basis of 200 g of silica gel (mobile phase: n-hexane and ethyl acetate 3: 2). After concentrating and drying the fractions with product, 17.0 g of oily dibenzylphosphonomethyl trifluoromethyl sulfonate were obtained.

Under a nitrogen atmosphere and to the exclusion of moisture, 16.5 ml of diisopropylamine were dissolved in 100 ml of dry THF and cooled to -70 ° C. To this mixture was added dropwise 65.5 ml of a 1.6 molar solution of n-butyllithium in n-hexane. Then it was left stirring at 0 ° C for 30 minutes, cooled to -20 ° C and at this temperature a solution of 5.3 ml of cyclopentanecarboxylic acid in 20 ml of THF was added dropwise. This reaction mixture was stirred first for 30 minutes at -20 ° C, then for 2 hours at 0 ° C, and then cooled to -60 ° C. To this mixture was slowly added dropwise 20.0 g of the product obtained in section B) in 20 ml of THF. After the addition was complete, it was stirred for 1 hour at -30 ° C and then for one hour at -20 ° C. The reaction mixture was then poured into an aqueous solution of ice cold potassium hydrogensulfate and extracted with methyl tere. -butyl ether (= MTBE). The organic phase was separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate and after filtration, concentrated in vacuo. The crude product obtained was purified by chromatography on 300 g of silica gel with pure MTBE, to which was added a proportion of methanol which was continuously increasing from 5% to 10%. The product thus obtained was chromatographed again on 200 g of silica for further purification, whereby 6.7 g of pure 1-dibenzylphosphonomethyl-1-cyclopentanecarboxylic acid, p. F. = 89-92 ° C.

D) To a solution heated at 65 ° C of 24.5 g of tere ester. 3-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid racemate in 50 ml of methanol was added a solution of 12.65 g of acid. L- (+) - tartaric in 54 ml of ethanol heated to 65 ° C. The reaction mixture was stirred for one hour at room temperature. Then a solution of 1.72 ml of benzaldehyde in 1.3 ml of ethanol was added thereto dropwise. The obtained suspension was boiled under reflux for 14 hours at 80 ° C and then cooled to room temperature. The resulting crystalline precipitate was filtered off with suction, taken up in 80 ml of ethanol and again boiled under reflux. It was then cooled to room temperature and the crystals were filtered with suction and dried at 50 ° C under reduced pressure. 23.6 g of a tartaric acid salt were obtained with a 2 200 melting point of 195 to 196 ° C; [] D D = -152.0 ° (c = 0.5 in methanol) E) To release the base, 23.6 g of the tartaric acid salt in a mixture of 250 ml of water and 108 ml of dichloromethane were cooled to 0 ° C with stirring and adjusted to pH 9.6 by addition of an aqueous solution of ammonia. The organic phase was separated, the aqueous phase was extracted again with 30 ml of dichloromethane and the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining residue was crystallized from MTBE and dried under reduced pressure. 12.2 g of tere ester were obtained. butyl (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid, p. F. = 113 20 115 ° C; [a] Dn ° -276.2 ° (c = 0.5 in methanol) F) 3.6 g of tere ester. - pure butyl in terms of the enantiomers, obtained previously, were combined with 2.8 g of p-toluenesulfonic acid and 6.9 ml of benzyl alcohol in 60 ml of toluene. Then, this mixture was boiled for 3 hours in a water separating apparatus, the toluene was removed in vacuo and the remaining residue was stirred with MTBE. After having separated the solvent by decantation, the residue was taken up in dichloromethane and stirred with a dilute aqueous solution of sodium carbonate, cooled by ice. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water. The organic phase was then dried over sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from MTBE and dried. 3.2 g of (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid benzyl ester, p. F. = 113 - 115 ° C; [a] ° = -236.8 ° (c = 0.5 in methanol] G) 5.8 g of the acid obtained above in section C) were taken up in 148 ml of dry dichloromethane. To the obtained solution were added, while cooling by ice, consecutively 4.8 g of the product obtained previously, 3.7 ml of N-methyl-morpholine, 1.84 g of 1-hydroxy-benzotriazole and 5.8 g of N- (3-dimethylamino-propyl) -N'-ethyl-carbodiimide hydrochloride. Then, the reaction mixture was allowed to stir at room temperature for 1 hour, with the exclusion of humidity. For the treatment, the reaction mixture was diluted with dichloromethane and washed consecutively with water, with an aqueous solution of potassium hydrogensulfate, with water, with an aqueous solution of sodium hydrogencarbonate and again with water. Drying of the organic phase over sodium sulfate and concentration by evaporation in vacuo gave 10.5 g of a crude product, which was purified by chromatography on 200 g of silica gel (eluent: n-hexane mixture). and ethyl acetate 3: 7). After concentrating the fractions with product by evaporation and drying in vacuo, 6.5 g of the pure title compound were isolated as a solid foam, IR: 3400, 3310, 2940, 1740, 1650 cm "1 ( film); [] D = -104.6 ° (c = 0.754 in methanol).

Example 2: (3S) -3- (1-Phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid A) 1.9 g of (3S) -3- (1-dibenzyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin benzyl ester -l-acetic (about its preparation, see Example 1G) were dissolved in 100 ml of ethanol. Thereto was added 1.2 g of a 5% palladium catalyst on activated carbon and hydrogenated for 3 hours at a hydrogen pressure of 5.5 bar. For the treatment, it was separated from the catalyst by filtration, concentrated by evaporation in vacuo and dried. 0.9 g of the title compound was obtained as a foamy product, IR: 3400, 1720, 1630 cm "1 (KBr); [] ° = -140.8 ° (c = 0.5 in methanol).

B) 701 mg of the free acid obtained above and 238 mg of sodium carbonate were dissolved in 60 ml of water and the solution was concentrated by evaporation in a vacuum. The residue obtained was taken up in a little MTBE and concentrated again by evaporation in vacuo. The solid foam, now obtained, was crystallized from isopropanol, the crystals were separated from the solvent and dried for 2 days under high vacuum at 60 ° C. 700 mg of the sodium salt of the title compound, p. F. > 270 ° C; [d] D = -159.7 ° (c = 0.149 in methanol).

Example 3; Benzyl ester of (3S) -3- (1-benzyl-ethyl-phosphono-ethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acé acid ico A) While cooling by ice, a solution of 8.0 g of NaOH in 30 ml of water and 30 ml of ethanol was added dropwise to 27.6 g of diethyl phosphite, and stirred for 2 hours at room temperature. ambient. It was then concentrated in vacuo and the aqueous residue extracted 4 times with MTBE. Concentration of the aqueous phase by evaporation in vacuo afforded 25.0 g of sodium ethyl-hydrogen phosphite as a white powder, which was reacted without further purification.

B) To a solution of 33.9 g of tetrabutylammonium hydrogensulfate in 20 ml of water was added dropwise while cooling by ice a solution of 4.0 g of NaOH in 22 ml of water, the temperature being maintained below of 25 ° C. Then 12.5 g of the product obtained above, dissolved in 15 ml of water, were added dropwise at room temperature. After stirring for 15 min, the precipitated sodium sulfate was separated by filtration with suction and the filtrate was extracted 4 times, each time with 50 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was dried at 40 ° C for 1 hour in vacuo, dissolved in 120 ml of anhydrous acetonitrile and mixed with 7.07 ml of benzyl bromide and 0.4 g of sodium iodide. It was left under stirring at 50 ° C for 12 hours, the solvent was removed in vacuo and the residue was taken up in n-hexane. It was separated from the solid residue by suction filtration, subsequently washed with a mixture of n-hexane and MTBE, and dried. The obtained solution was concentrated by evaporation in vacuo and the residue was chromatographed on 200 g of silica gel (eluent: mixture of n-hexane and acetic acid ethyl ester 2: 3). 6.7 g of benzyl ethyl phosphite was obtained as an oil, IR: 2420, 1255, 970 c "1 (movie) .

C) 18.0 g of the above product were reacted with 2.5 g of paraformaldehyde and 1.2 ml of triethylamine, as indicated in Example 1A). Chromatography on 200 g of silica gel (eluent: ethyl acetate) gave 16.5 g of benzyl ethyl hydroxymethyl phosphonate as an oil, IR: 3300, 1230, 1030 cm "1 (film).

D) 12.0 g of the product obtained above were reacted with 6.2 g of 2,6-lutidine and 9.0 ml of trifluoromethanesulfonic acid anhydride, as described in Example IB). Chromatography on 200 g of silica gel (eluent: mixture of n-hexane and acetic acid ethyl ester 2: 3) gave 16.3 g of benzyl ethyl phosphonomethyl trifluoromethylsulfonate, IR: 1410, 1245, 1210, 1010 cm "(film).

E) From 16.08 ml of diisopropylamine, 63.8 ml of a 1.6 molar solution of n-butyl lithium in n-hexane and .3 ml of cyclopentanecarboxylic acid, the dianion of the cyclopentanecarboxylic acid was prepared according to the method described in Example 1C) and, as described therein, was reacted with 16.0 g of the product obtained above in section D) . Chromatography of the crude product on 300 g of silica gel (eluent: first a mixture of n-hexane and 1: 1 ethyl ester of acetic acid, which was gradually replaced by ethyl acetate of pure acetic acid) yielded 7.1 g of oily and pure l- (benzyl-ethyl-phosphonomethyl) -1-cyclopentanecarboxylic acid, IR: 2950, 1720, 1210, 1175, 1010 cm "1 (film). 3.1 g of the acid obtained above were reacted with 3.2 g of benzyl ester of (3S) -3-amino-2, 3,4,5-tetrahydro-2-oxo-lH-1-benzazepin-1 acid. - acetic (about its preparation, see Example 1F)), 3.3 ml of N-methyl-morpholine, 1.35 g of hydroxybenzotriazole and 3.8 g of N- (3-dimethylamino-propyl hydrochloride ) -N'-ethylcarbodiimide, according to the method described in Example 1G). Chromatography on 200 g of silica gel (eluent: acetic acid ethyl ester) gave 2.3 g of the title compound as a viscous oil, IR: 3410, 2940, 1735, 1660, 1230, 1020 cm "1 ( KBr); [t] ^ ° = -121.6 ° (c = 0.495 in methanol).

Example 4; Ethyl ester of (3S) -3 - (1-benzyl-ethyl-phosphonomethyl-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2 -oxo-lH-l-benzazepin-1- acetic A) 5.0 g of ester tere were boiled in a water separating apparatus. butyl (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid (about its preparation, see Example 1E)) and 3.75 g of p-toluenesulfonic acid in 80 ml of toluene for 2.5 hours. After that, 200 ml of ethanol were added in portions and the resulting reaction mixture was boiled under reflux for 3.5 hours. Then, the mixture was concentrated in vacuo and the residue was taken up in dichloromethane. It was then stirred with an ice-cooled solution of sodium carbonate and the organic phase was washed neutral with water. The organic phase was dried over sodium sulfate, concentrated by evaporation in vacuo and the remaining residue was dried. 3.6 g of (3S) -3-amino-2, 3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid ethyl ester, p. F. = 106.5 ° - 108 ° C; IR = 3350, 3300, 2930, 1735, 1660 cm "1 (film); [a] ^ 0 = -288.4 ° (c = 0.5 in methanol).

B) 3, 1 g of 1- (benzyl-ethyl-phosphonomethyl) -1-cyclopentanecarboxylic acid (about its preparation, see Example 3E)) were reacted with 2.6 g of the product obtained above, 3, 3 ml of N-methyl-morpholine, 1.35 g of hydroxy-benzotriazole and 3.8 g of N- (3-dimethylamino-propyl) -N'-ethylcarbodiimide hydrochloride, according to the method described in Example 1G). Chromatography on 200 g of silica gel (eluent: first, a mixture of n-hexane and ethyl acetate 1: 1, which was continuously modified until the composition was 3: 7) gave 3, 7 g of the title compound as an oil, IR: 3410, 2950, 1735, 1660 cm "1 (film); [] D 20 = -113.6 ° (c = 0.639 in methanol).

Example 5; Ethyl ester of (3S) -3- (1-ethyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid 3.2 g of ethyl ester of (3S) -3- (1-benzyl-ethyl-phosphonomethyl-cyclopent-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l -benzazepin-1-acetic (about its preparation, see Example 4) were mixed with 1.0 g of a 5% palladium catalyst on activated carbon and hydrogenated at a hydrogen pressure of 2.2 bar, according to the method described in Example 2). The treatment afforded 2.4 g of the title compound as a foamed resin, IR: 3400, 2950, 1740, 1650 cm "1; [a] D -162.0 ° (c = 0.324 in methanol).

Example 6; Ethyl ester of (3S) -3 - [1- (pivaloyloxymethyl-ethylphosphonomethyl) -cyclopentane-1-carbonylamino] -2,3,4,5-tetrahydro-2 -oxo-lH-benzazepin-1-acetic acid 0.6 g of ethyl ester of (3S) -3- (1-ethyl-phosphonomethyl-5-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l- benzazepin-1-acetic acid (about its preparation, see Example 5) were dissolved under exclusion of moisture in 20 ml of DMF and then mixed with 1.86 ml of triethylamine, 0.88 ml of pivaloyloxymethyl chloride and 0. , 1 g of dimethylamino-pyridine. The reaction mixture was allowed to continue to stir overnight, the solvent was removed by evaporation under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water and then dried over sodium sulfate. Concentration in vacuo gave a crude product, which was chromatographed on 50 g of silica gel for the purification (eluent: initially a mixture of n-hexane and ethyl acetate 3: 7, the proportion of ester being increased gradually up to 100 %) . 188 mg of the title compound were obtained as an oil, IR = 1740, 1650 cm "1 (CH2C12); [] ° = -124.1 ° (c = 0.288 in methanol).

Example 7: (3S) -3 - [1- (5-indanyl-ethyl-phosphono-methyl) -cyclopentane-1-carbonylamino] -2, 3, 4, 5-tetrahydro-2-oxo-3-ethyl ester 1H-benzazepin-1-acetic 480 mg of ethyl ester of (3S) -3- (1-ethyl-phosphonomethyl-cyclopentane-1-carbonyl amino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-l acid ester -acetic (about its preparation, see Example 5) were dissolved in 10 ml of dry dichloromethane and mixed with 0.28 ml of triethylamine. This solution was cooled to -50 ° C, and then 0.09 ml of oxalyl chloride was added. Then, the reaction mixture was mixed at -50 ° C with 200 mg of 5-indanol, allowed to warm to 0 ° C and stirred for 5 hours at room temperature. The organic phase was washed with water, separated, dried over sodium sulfate and concentrated by evaporation under reduced pressure. Chromatography on 80 g of silica gel (eluent: mixture of n-hexane and acetic acid ethyl ester 1: 1, the ratio of solvents being modified in a continuous manner to 1: 4) and drying under high vacuum provided 220 mg of the title compound as a viscous resin, IR: 1740, 1655 cm "1 (CH2Cl2); [0-] D = -135.1 ° (c = 0.205 in methanol).

Example 8; Ester tere. -butylic acid (3S) -3- (1-benzyl-ethyl-phosphono-methyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1- acetic .0 g of 1- (benzyl-ethyl-phosphonoethyl) -1-cyclopentanecarboxylic acid (about its preparation, see Example 3E)) were reacted with 5.15 g of tere ester. -butylic acid (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-lH-1-benzazepin-1-acetic acid (about its preparation, see Example 1E), 4.1 m of N-methyl-morpholine, 2.0 g of hydroxy-benzotriazole and 6.3 g of N- (3-dimethylamino-propyl) -N1-ethylcarbodiimide hydrochloride corresponding to the method described in Example 1G) . The obtd crude product was chromatographed on 200 g of silica gel (eluant: first a mixture of n-hexane and 1: 1 ethyl ester of acetic acid, then the pure ester). 2.6 g of the title compound were obtd as a foamed resin, IR = 3410, 3350, 1735, 1655 cm "1; [? L] 2D ° = -118.1 ° (c = 0.609 in methanol).

Example 9: (3S) -3 - (1-Ethyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid benzyl ester A) 3.5 g of 1- (benzyl-ethyl-phosphonomethyl) -1-cyclopentanecarboxylic acid (about its preparation, see Example 3E)) were dissolved in 150 ml of ethanol and mixed with 1.0 g. of a 5% Pd catalyst on activated carbon. Then it was hydrogenated for 4 hours at a hydrogen pressure of 2.1 bar. It was separated from the catalyst by filtration twice, concentrated by evaporation in vacuo and dried under high vacuum. 2.60 g of oily 1-ethyl-phosphono-methyl-1-cyclopentanecarboxylic acid were obtd, which was reacted without further purification.

B) 2.6 g of the product obtd above were dissolved, with the exclusion of moisture, in 100 ml of dry dichloromethane and mixed with 3.5 g of carbonyl-diimidazole and 3.56 g of benzyl ester of (3S) acid. 3-amino-2, 3,4,5-te rahydro-2-oxo-lH-l-benzazepin-1-acetic acid (on its preparation, see Example 1F)) and stirred overnight. It was then poured into a saturated aqueous solution of potassium hydrogensulfate, the organic phase was washed neutral with water and dried over sodium sulfate. The obtd crude product was chromatographed on 150 g of silica gel (eluent: first ethyl ester of acid • acetic, to which dichloromethane was gradually added until reaching a solvent ratio of 1: 1). After having dried in vacuo the fractions with product, 1.4 g of the title compound was obtd as a solid foam, IR 3410, 1740, 1645 cm • 1-200 (KBr); [Q] DD = -130.7 ° c = 0.339 in methanol). 10 Example 10; Benzyl ester of (3S) -3- (1-diethyl-phosphonomethyl-1-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid A ) 69.05 g of diethyl phosphite were reacted with 14, 5 g of paraformaldehyde and 6.96 ml of triethylamine, analogously to the procedure described in Example 1A). 66.02 g of diethyl-20-hydroxymethyl-phosphonate were obtained, which after being dried under high vacuum was reacted further without further purification. • B) 21.02 g of the above-obtained phosphonate, 15.0 g of 2,6-lutidine and 21.8 ml of trifluoromethanesulfonic acid anhydride were reacted in the manner described in Example IB). 32.5 g of oily diethyl phosphonomethyl trifluoromethylsulfonate were obtained. 30 C) 30.0 g of the above-obtained trifluoromethylsulphonate were reacted with 133 ml of a 1.6 molar solution of n-butyllithium in n-hexane and 10.8 ml of cyclopentanecarboxylic acid, as described. in Example 1C). 11.1 g of diethylphosphonomethyl-1-cyclopentanecarboxylic acid were obtained, IR: 2970, 1730, 1240, 1030 cm "1 (film) D) 5.74 g of the above-obtained carboxylic acid derivative were reacted with 7.05 g of benzyl ester of (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-lH- 1-benzazepin-1-acetic (about its preparation, see Example 1F)), according to the method described in Example 1G). The obtained crude product was purified by chromatography on silica gel (eluent: ethyl acetate). 7.95 g of the title compound were obtained, IR = 3400, 1745, 1650 cm "1 (film); [cx] ° = -130.3 ° (c = 0.538 in methanol).

Example 11; (3S) -3- (1-Diethyl-phosphonomethyl-cyclopentane-1-carbonyl-a-ino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid .3 g of benzyl ester of (3S) -3- (1-diethyl-phosphonome-il-1-cyclopentane-1-carbonyl amino) -2,3,4,5-tetrahydro-2-oxo-lH-benzazepin- L-acetic (about its preparation, see Example 10) were dissolved in 250 ml of ethanol, mixed with 1.5 g of a 5% Pd catalyst on activated carbon and hydrogenated according to the method described in Example 2. 4.3 g of the title compound, IR 3390, 1730, 1650 c -1 (KBr) were obtained 2 20 [] DD = -156.6 ° (c = 0.514 in methanol) Example 12; Ethyl ester of (3S) -3 - (1-diethylphosphonyl ethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-1-benzazepin-1 - acetic 2.34 g of (3S) -3- (1-diethyl-p-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid (about its preparation, see Example 11) were dissolved under exclusion of moisture in dichloromethane, mixed with 1.6 ml of N-methyl-orpholine, 0.63 g of 1-hydroxy-benzotriazole, 2.0 g of N- (3-dimethylamino-propyl) -N 1 -ethyl-carbodiii-da hydrochloride and 0.6 ml of ethanol and stirred for 4 hours at room temperature. Then, the reaction mixture was washed consecutively with water, with a solution of potassium hydrogensulfate, with water, with a solution of sodium hydrogencarbonate and again with water. The organic phase was then separated, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting product was chromatographed on 200 g of silica gel (eluent: initially acetic acid ethyl ester, subsequently supplemented by the addition of 5% methanol), the product fractions were concentrated and dried in vacuo. 1.6 g of the title compound were obtained, IR = 3410, 1740, 1650, 1200, 1030 cm "1 (film); [a] ^ ° = -126.1 ° (c = 0.584 in methanol).

Example 13; Ethyl ester of (3S) -3- (1-phosphonomethyl-cyclopentane-l-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-l-acetic acid 1.3 g of ethyl ester of (3S) -3- (1-diethyl-phosphonomethyl-cyclopentane-1-carbonyl amino) -2,3,4,5-tetrahydro-2-oxo-lH-1-benzazepin- L-acetic (about its preparation, see Example 12) were dissolved under a nitrogen atmosphere in 13 ml of dry dichloromethane. While cooling by ice, 0.5 ml of bromo trimethylsilane and 0.4 ml of triethylamine were added and allowed to stir overnight. The excess solvent was removed in vacuo and the residue was stirred for 15 minutes in aqueous acetone. The residue which remained after the solvent was removed by evaporation was taken up in MTBE, to which a little dichloromethane had been added, and mixed with 0.53 g of (S) - (-) -a-methyl- benzyl amine. The precipitated solid material was recrystallized once from ethanol, yielding the title compound as the ct-methyl-benzyl-ammonium salt of p. F. = 210-213 ° C. IR = 2940, 1750, 1650, 1200, 1045 cm "1 (KBr); [a] ° = -141.0 ° (c = 0.2 in methanol).

Example 14; Benzyl ester of (3S) -3- (l-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid benzyl ester 3.8 g of (3S) -3- (1-diethylphosphonomethyl-1-cyclopentane-1-carbonylamino) -2-benzyl ester, 3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic (about its preparation, see Example 10) were dissolved in 10 ml of dichloromethane, mixed by means of ice cooling with 10.3 ml. of trifluoroacetic acid and then stirred for 18 hours at room temperature. The solvent was removed in vacuo and the remaining residue was taken up several times with toluene and in each case concentrated again by evaporation. The obtained crude product was dissolved in dichloromethane and washed 3 times with water, then the organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation in vacuo. Drying in high vacuum afforded 3.0 g of the title compound as an oil, IR = 3400, 2950, 1745, 1640 cm "1 (KBr), [a] ß ° = -146.5 ° (c = 0, 2 in methanol).

Example 15; Benzyl ester of (3S) -3- (1-diisopropyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid A) 50.0 g of diisopropylphosphite, 8.5 g of paraformaldehyde and 4.0 ml of triethylamine were reacted according to the method indicated in Example 1A). Chromatography of the crude product on silica gel (eluent: mixture of n-hexane and ethyl acetate 1: 4) gave 37.5 g of diisopropyl-hydroxymethyl phosphonate as an oil, which was reacted further without purification .

B) 19.6 g of the compound obtained above were reacted with 17.4 ml of trifluoromethanesulfonic acid anhydride and 11.96 g of 2,6-lutidine, in the manner described in Example IB). Chromatography of the crude product on silica gel (eluent: mixture of n-hexane and ethyl acetate 3: 7) gave 27.4 g of diisopropyl-phosphonomethyl trifluoromethylsulfonate as an oil, IR = 2980, 1410, 1205 , 1000 cm "1 (film).

C) 27.4 g of the above-obtained compound, 10.05 ml of cyclopentanecarboxylic acid and 120 ml of a 1.6 molar solution of n-butyllithium in n-hexane were reacted according to the method described in Example 1 C) . Chromatography of the crude product on silica gel (eluent: first a mixture of n-hexane and 3: 7 ethyl acetate, to which increasing portions of ester were added gradually to 100%) provided 10.6 g of diisopropyl-phosphonomethyl-1-cyclopentanecarboxylic acid from p. F. = 53-57 ° C. 2.05 g of the above-obtained compound were reacted with 2.24 g of (3S) -3-amino-2, 3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1 benzyl ester. -acetic (about its preparation, see Example 1F)) according to the method described in Example 1G). 3.5 g of the title compound were obtained as an oil, IR = 3410, 1735, 1650, 1240, 1180 cm "1 (film); [a] D ° = -127.5 ° (c = 0.287 in methanol) Example 16; Ethyl ester of (3S) -3 - (1-benzyl-isopropyl-phosphono-methyl-cyclopentane-1-carbonylamino) -2, 3,4, 5-tetrahydro-2-oxo-lH-l-benzazepin-1- acetic A) 92.0 ml of diisopropylphosphite and 22.2 g of NaOH were reacted as described in Example 3A). 88.0 g of sodium isopropyl hydrogen phosphite were obtained, which was reacted without further purification.

B) 88.0 g of the compound obtained above and 34 ml of benzyl bromide were reacted analogously to the method described in Example 3B). 46.3 g of benzyl isopropylphosphite was obtained as an oil, which was reacted without further purification.

C) 46.3 g of the above-described compound were reacted with 6.1 g of paraformaldehyde and 2.87 ml of triethylamine, according to the method described in Example 1A). 24.0 g of benzyl-isopropyl-hydroxymethyl phosphonate were obtained as an oil, IR = 3300, 1230, 995 cm "1 (film).

D) 24.0 g of the compound obtained above were reacted with 18.01 ml of trifluoromethanesulfonic acid anhydride and 13.57 ml of 2,6-lutidine, according to the method described in Example IB). 32.5 g of benzyl-isopropyl-phosphonomethyl trifluoromethylsulfonate were obtained as an oil, IR = 2980, 1410, 1245, 1000 cm "1 (film).

E) 32.5 g of the compound obtained above, 9.65 ml of cyclopentanecarboxylic acid and 13.4 ml of a 1.6 molar solution of n-butyl lithium in hexane were reacted according to the method described in Example 1 C) . Chromatography of the crude product on silica gel (eluent: firstly a mixture of n-hexane and ethyl acetate 1: 1, and then the pure ether, then ethyl acetate with 5% by volume of isopropanol ) gave 7.0 g of 1-benzyl-isopropyl-phosphonomethyl-1-cyclopentanecarboxylic acid, which was reacted without further purification.

F) 1.25 g of the above-described compound and 1.06 g of (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-ethyl ester. acetic (about its preparation, see Example 4A) were reacted according to the method described in Example 1G). 0.68 g of the title compound were obtained, IR = 2400, 1735, 1655, 1200, 985 cm "(film 20); [í] D = -123.0 ° (c = in isopropanol).

And 17; Ester tere. -butyl (3S) -3- (1-ethyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid 2.2 g of ester tere. -butyl (3S) -3- (l-benzyl-ethyl-phosphonomethyl-cyclopentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-l-acetic acid ( about its preparation, see Example 8)) were hydrogenated with 1.0 g of a 5% Pd catalyst on activated carbon, according to the method indicated in Example 2, at a hydrogen pressure of 2.5. pubs. 1.7 g of the title compound were obtained, IR = 3400, 1735, 1650 cm -1 (film) [a] -158.2 ° (c = 0.515 in methanol).

Example 18; Ester tere. -butylic acid (3S) -3 - [1- (pivaloyloxymethyl-ethyl-phosphonome-yl) -cyclopentane-1-carbonylamino] -2,3,4,5-tetrahydro-2 -oxo-lH-benzazepin-1-acetic acid 0.6 g of ester tere. -butyl (3S) -3- (1-ethyl-phosphonomethyl-cyclopentane-1-carbonyl-amino) -2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid (about its preparation, see Example 17) were reacted with 1.73 ml of triethylamine, 0.86 ml of pivaloyloxymethyl chloride and 0.1 g of dimethylamino-pyridine, according to the method indicated in Example 6. After chromatography on silica gel (eluent: acetic acid ethyl ester), 392 mg of the title compound were obtained as a viscous resin, IR = 1740, 1650 c "1 (CH2Cl2); [& ] D = -122.9 ° (c = 0.257 in methanol).

About Example 20 (3S) -3 - (1-Phosphonomethyl-cyclo-pentane-1-carbonylamino) -2,3,4,5-tetrahydro-2-oxo-lH-1-benzazepin-tert -butyl ester 1-acetic: forms of salts A) 961 mg of the above-mentioned free phosphonic acid were mixed with 212 mg of sodium carbonate and 20 ml of water. The resulting mixture was filtered and the obtained filtrate was concentrated by evaporation in vacuo. The residue obtained was crystallized from ethanol and the crystals were dried under vacuum at 60 ° C for one day. 750 mg of a sodium salt of the title compound, e.g. F. = > 270 ° C, [a] D = -141.5 ° c = 0.25 in methanol). 961 mg of the above-mentioned free phosphonic acid were dissolved in 20 ml of MTBE and mixed with 0.42 ml of tere. -butylamine. The resulting solution was concentrated by evaporation in vacuo and the obtained residue was taken up in a mixture of NTBE and n-hexane. The resulting crystals in this solvent mixture were separated and dried at 60 ° C in vacuo. 950 mg of ammonium salt was obtained from the compound of 20%, pp .. ff .. == 215 ° -220 ° C; [? í] 149.8 ° (c 0.26 in methanol) In accordance with the procedures described in the preceding Examples, the compounds of Formula I which are indicated in the following Table 3 can also be prepared.

Table 3 = ecilo; tBu = tere. -butyl; POM = pivaloyloxymethyl; = 5-indanyl; Bn = benzyl; 1Pr = isopropyl E emplo I; Capsules containing ester tere. -butyl (3S) -3- [1- (pivaloyloxymethyl-ethyl-phosphonomethyl) -cyclopentane-1-carbonylamino] -2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid: Capsules with the following composition per capsule were prepared: Ester tere. -butylic acid (3S) -3- [1- (pivaloyloxymethyl-ethyl-phosphonomethyl) -cyclopentane-1-carbonylate] -2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-1-acetic acid 20 mg Corn starch 60 mg Lactose 301 mg Ethyl acetic acid ester cs The active substance, corn starch and lactose were prepared, using acetic acid ethyl ester, to form a homogenous paste mixture. The paste was crumbled and the resulting granulate was placed on an appropriate sheet and, for solvent removal, dried at 45 ° C. The dried granules were passed through a shredder and mixed with the following adjuvants in a mixer: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then loaded into capsules with a capacity of 400 ~ g (= size of capsules 0).

R110-Y Goes And Vb R 310 • Y Ve

Claims (3)

1. Claims Compounds of the general Formula I wherein R means hydrogen or a group forming a biolabile phosphonic acid ester, R means hydrogen or a group forming a biolabile phosphonic acid ester, and R3 means hydrogen or a group forming a biolabile carboxylic acid ester, and physiologically compatible salts of acids of Formula I.
2. 2. Compounds according to claim 1, wherein RJ means hydrogen or lower alkyl.
3. 3. Medicaments, which contain a pharmacologically effective amount of a compound according to claim 1 and customary pharmaceutical adjuvants and / or vehicle substances. -i. - Procedure for the preparation of compounds of General Formula I wherein R means hydrogen or a group forming a biolabile phosphonic acid ester, R means hydrogen or a group forming a biolabile phosphonic acid ester, and R3 means hydrogen or a group forming a biolabile carboxylic acid ester, and physiologically compatible salts of acids of the Formula I, characterized in that: a) for the preparation of compounds of the general Formula IV wherein R101 and R201 in each case independently of one another denote hydrogen or a phosphonic acid protecting group and R-302 means a carboxylic acid protecting group, compounds of the general Formula II are reacted wherein R101 and R201 possess the above meanings, with compounds of the general Formula III wherein R302 has the above meaning and, if R101 and / or R201 mean hydrogen, the free phosphonic acid (s) (s) function (s) are transformed if desired by esterification with a compound of the general formulas Va and / or Vb R110_? (Go) R210_? (Vb) wherein R110 and R2-1-0 in each case mean a group forming a biologically inactive phosphonic acid ester and Y means hydroxy or a separable labile group, in groups of biolabile phosphonic acid esters, and if in the compounds of the Formula IV the protecting groups R10, R2 ^ and / or R (^ do not represent any of the groups forming biolábile esters, these are separated simultaneously or individually consecutively in any order of succession, and if desired the functions of The acids liberated in each case are transformed into groups of biologically inactive esters, esterifying the functions of free phosphonic acids with a compound of the formula Va or Vb and / or esterifying the free carboxylic acid function with a compound of the general formula. R310_? (Go) wherein Ro u means a group that forms esters of biolabile carboxylic acids and Y has the above meaning, and if desired, acids of the Formula I are transformed into their physiologically compatible salts or salts of the acids of the Formula I are converted into the free compounds.