HK1019338B - Phosphonic acid-substituted benzazepinone-n-acetic acid derivatives, and processes for their preparation and pharmaceuticals comprising these compounds - Google Patents

Description

Phosphonic acid substituted benzazepinone-N-acetic acid derivatives, process for their preparation and medicaments

The invention relates to novel benzazepine-N-acetic acid derivatives which are substituted in the 3-position by a cyclopentylcarbonylamino group which carries a methylphosphonic acid residue in the 1-position, to their salts and to biologically labile esters, to pharmaceutical preparations containing these compounds and to processes for preparing these compounds.

Phenylazepine-, benzoazepine-and benzodiazepine-N-acetic acid derivatives are known from european patent application, publication No. 0733642, which have an inhibitory effect on neutral endopeptidase (═ NEP).

The object of the present invention is to develop novel pharmacologically active substances with an NEP-inhibiting action which have a favourable effect in the treatment of heart failure and hypertension.

It has now been found that the novel benzazepinone-N-acetic acid derivatives of the invention, which are substituted in the 3-position of the benzazepinone-skeleton by a cyclopentylcarbonylamino group carrying a methylphosphonic acid residue in the 1-position, have very valuable cardioactive pharmacological properties, have a particularly advantageous effect in the treatment of cardiovascular diseases, in particular heart failure, and at the same time have an excellent inhibitory effect on neutral endopeptidase and on endothelin converting enzyme (═ ECE) and good tolerability.

The object of the present invention is to provide novel compounds of the general formula I, physiologically tolerated salts of acids of the general formula I, processes for preparing these compounds and medicaments containing these compounds

Wherein

R¹Hydrogen or a group capable of forming a biologically labile phosphonate,

R²hydrogen or a group capable of forming a biologically labile phosphonate,

R³hydrogen or a group capable of forming a biologically labile carboxylate.

The compounds of formula I are acid derivatives containing carboxylic acid-and phosphonic acid groups, optionally esterified with groups that form biologically labile esters. The biostable ester of formula I is a precursor to the free acid. The biologically labile ester or acid is preferred by the mode of administration, the latter being particularly suitable for intravenous injection.

As groups R capable of forming biologically labile phosphonates¹And R²Suitable are groups which can be cleaved at the same time as the corresponding phosphonic acid functions are released under in vivo physiological conditions. For example, C as herein suitable is lower alkyl, optionally substituted on the oxymethyl group by lower alkyl₂-C₆-alkanoyloxymethyl or phenyl lower alkyl, the phenyl ring of which is optionally substituted one or more times by lower alkyl, lower alkoxy or by a lower alkylene chain bound to two adjacent carbon atoms. If the group R of the biolabile ester is formed¹And/or R²Is or contains a lower alkyl group, it may be branched or straight-chain and contain 1 to 4 carbon atoms. If R is¹And/or R²Is an optionally substituted alkanoyloxymethyl group, it may then contain a preferably branched alkanoyloxy group having 2 to 6, preferably 3 to 5, carbon atoms, and may be, for example, a pivaloyloxymethyl residue (═ tert-butylcarbonyloxymethyl residue). If R is¹And/or R²Is an optionally substituted phenyl lower alkyl group, it may then contain an alkylene chain with 1 to 3, preferably with 1, carbon atom. If the phenyl ring is substituted by a lower alkylene chain, it may contain 3 to 4, especially 3, carbon atoms, the substituted phenyl ring being especially a 2, 3-indanyl group.

As groups R capable of forming biologically labile carboxylic esters³Suitable are groups which can be cleaved at the same time as the corresponding carboxylic acid is released under in vivo physiological conditions. For example, phenyl or phenyl lower alkyl optionally substituted on the phenyl ring one or more times by lower alkyl or lower alkoxy, or by a lower alkylene chain bound to two adjacent carbon atoms, dioxolanyl methyl optionally substituted by lower alkyl on the dioxolane ring or C optionally substituted by lower alkyl on the oxymethyl ring, are suitable herein₂-C₆-alkanoyloxymethyl. If the group R of the biolabile ester is formed³Is or contains a lower alkyl group, it may be branched or straight-chain and contain 1 to 4 carbon atoms. If the group capable of forming a biolabile ester is optionally substituted phenyl lower alkyl, it may contain an alkylene chain carrying 1 to 3, preferably 1, carbon atoms, and is preferably benzyl. If the phenyl ring is substituted by a lower alkylene chain, the latter may contain 3 to 4, preferably 3, carbon atoms. If R is³Is an optionally substituted alkanoyloxymethyl group, the latter then contains a preferably branched alkanoyloxy group which carries 2 to 6, preferably 3 to 5, carbon atoms and may be, for example, a pivaloyloxymethyl group.

According to the invention, the novel compounds of the formula I and their salts are obtained in a manner known per se by

a) To prepare compounds of the formula IV

Wherein R is¹⁰¹And R²⁰¹Each independently of the others being hydrogen or a phosphonic acid protecting group, R³⁰²For a carboxylic acid protecting group, a compound of formula II

Wherein R is¹⁰¹And R²⁰¹Having the above-mentioned meaning, with a compound of the general formula III,

wherein R is³⁰²Has the above-mentioned meaning, and, if R is¹⁰¹And/or R²⁰¹The free phosphonic acid function is optionally esterified for hydrogen by means of compounds of the formula Va and/or Vb,

R¹¹⁰-Y(Va) R²¹⁰-Y(Vb)

wherein R is¹¹⁰And R²¹⁰Each being a group capable of forming a biologically labile phosphonate ester, Y being a hydroxyl group or a cleavable leaving group, into a biologically labile phosphonate ester group

b) If in the compounds of the formula IV the protecting group R¹⁰¹、R²⁰¹And/or R³⁰²Not the desired group capable of forming the biolabile ester, the latter are cleaved off simultaneously or separately in any order

Optionally, each free acid function is then converted into a biologically labile ester group by esterification of the free phosphonic acid function with a compound of the formula Va or Vb and/or by esterification of the free carboxylic acid function with a compound of the formula Vc,

R³¹⁰-Y (Vc)

wherein R is³¹⁰Is a group which forms a biologically labile carboxylate, Y has the meaning indicated above, and optionally the acid of the formula I is converted into a physiologically tolerable salt or the salt of the acid of the formula I is converted into the free compound.

As physiologically tolerated salts of the acids of the general formula I there come into consideration, respectively, the alkali metal, alkaline earth metal or ammonium salts thereof, for example the sodium, potassium or calcium salts thereof, or the salts with the following amines: i.e. with physiologically tolerated, pharmacologically neutral organic amines, such as diethylamine, tert-butylamine or phenyl lower alkylamines, such as α -methylbenzylamine.

As phosphonic acid protecting groups R¹⁰¹And R²⁰¹It is possible to select the protecting groups customary for protecting phosphonic acid functions, which are then cleaved again in a manner known per se. As carboxylic acid protecting groups R³⁰²The protecting groups customary for protecting carboxylic acid functions can be chosen, which can then be cleaved again in a manner known per se. Suitable carboxylic acid protecting groups are known, for example, from the following documents: McOmie in "organic chemistry"protective group" of (1), "Plenum Press, and Green, Wuts," protective group in organic Synthesis "published by Wiley Interscience. Suitable phosphonic acid protecting groups are known, for example, from the following documents: houben, Weyl "methods of organic chemistry" G.Thieme Press, Stuttgart, New York, 1982, pp.313-. As acid protecting groups it is also possible to use groups which form biologically labile esters. The compounds of the formula IV obtained in the conversion reaction of the compounds of the formula II with the compounds of the formula III are in this case already esters of the formula I according to the invention.

According to the invention, suitable phosphonic acid protecting groups R¹⁰¹And R²⁰¹Having groups which, independently of one another and in a suitable manner, are reactive with the carboxylic acid protecting groups R still present in the molecule³⁰²Independently selectively cleaved or selectively introduced. In general, the phosphonic acid protecting group is readily selectively cleaved in the presence of the carboxylic acid protecting group by trimethylsilyl bromide. Examples of phosphonic acid protecting groups which are cleavable under various conditions-which may also be groups which generate biologically labile phosphonates-are as follows: linear lower alkyl groups such as ethyl, which are for example susceptible to cleavage by acids such as trifluoroacetic acid, in which case if two phosphonic acid functions are esterified with a lower linear alkyl group, only one of the alkyl groups is cleaved under basic conditions. Branched lower alkyl groups such as t-butyl, which are readily cleaved under acidic conditions, for example by the action of trifluoroacetic acid. Phenylmethyl optionally substituted in the phenyl ring, such as benzyl, is readily cleaved by hydrogenolysis. Alkanoyloxymethyl groups such as pivaloyloxymethyl, which are readily cleaved by, for example, an acid such as trifluoroacetic acid. Phenylmethyl substituted once or more than once by lower alkoxy in the phenyl ring, such as p-methoxybenzyl, which CAN be readily cleaved under oxidative conditions, for example under the action of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (═ DDQ) or ammonium nitrite (═ CAN).

As carboxylic acid protecting groups R³⁰²Suitable are groups which are selectively cleaved or selectively introduced independently of carboxylic acid protecting groups which may be present in the molecule. The carboxylic acid protecting group which is cleavable under various conditions-it may also be a group capable of yielding a biologically labile carboxylate-may be exemplified by the following: linear lower alkyl groups such as ethyl, which are relatively easily cleaved under basic conditions. Branched lower alkyl groups such as t-butyl, which are readily cleaved by acids such as by trifluoroacetic acid. Phenylmethyl optionally substituted in the phenyl ring, such as benzyl, which is readily cleaved by hydrogenolysis or also under basic conditions. Phenylmethyl substituted one or more times in the phenyl ring by lower alkoxy, such as p-methoxybenzyl, is relatively easily cleaved under oxidative conditions, for example under the action of DDQ or CAN.

The compounds of formula I contain one chiral carbon atom, i.e. the carbon atom carrying the amide side chain in the 3-position of the benzazepine-backbone. Thus, these compounds may exist in the form of two optically active stereoisomers or as racemates. The present invention encompasses both racemic mixtures and isomerically pure compounds of the general formula I. If in the compounds of the formula I R¹And R²Instead of hydrogen, the phosphine atoms of the phosphonic acid groups can also be chiral, each having a different meaning. Mixtures of isomers which occur via the chiral phosphine atom and isomerically pure compounds of the general formula I are also an object of the present invention.

The reaction of the acid of the formula II with the amine of the formula III to give the amide of the formula IV can be carried out in accordance with the customary methods for amide formation by aminoacylation. As acylating agents it is possible to use carboxylic acids of the general formula II or reactive derivatives thereof. Mixed anhydrides and acid halides come into consideration in particular as reactive derivatives. Thus, for example, acid chlorides or acid bromides of the acids of the formula II or mixed esters of the acids of the formula II with organic sulfonic acids, such as: lower alkylsulfonic acids optionally substituted by halogen such as methanesulfonic acid or trifluoromethanesulfonic acid; or aromatic sulfonic acids such as benzenesulfonic acid; or a benzenesulfonic acid substituted with lower alkyl or halogen such as toluenesulfonic acid or bromobenzenesulfonic acid. The acylation reaction may be carried out in an organic solvent which is inert under the reaction conditions, at a temperature between-20 ℃ and room temperature. As the solvent, a halogenated hydrocarbon such as dichloromethane, or an aromatic hydrocarbon such as benzene or toluene, or a cyclic ether such as tetrahydrofuran (═ THF) or dioxane, or a mixed solvent of these solvents is suitable.

It is suitable, in particular when using mixed anhydrides of acids of the formula II as acylating agents, to carry out the acylation reaction in the presence of an acid-binding agent. Suitable as acid scavengers are, for example, organic bases which are soluble in the reaction mixture, such as tertiary nitrogen bases, for example tertiary-lower alkylamines, and pyridines, for example triethylamine, tripropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-pyrrolidinopyridine. The organic base added in excess can also act as a solvent at the same time.

If the acid of the formula II is used as acylating agent per se, the conversion of the amino compound of the formula III with the carboxylic acid of the formula II can advantageously be carried out in the presence of a known coupling reagent which is regarded by peptide chemistry as suitable for amide formation. Coupling agents capable of promoting the formation of amides with the free acids in such a way that they react with the acids at the same time as the formation of a reactive acid derivative in situ may be cited, as coupling agents there being mentioned, inter alia, alkyldiimidazoles, such as cycloalkylcarbodiimides, for example dicyclohexylcarbodiimide, or N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide, carbonyldiimidazole, and N-lower alkyl-2-halopyridinium salts, in particular halides or tosylates. The conversion reaction in the presence of a coupling agent can advantageously be carried out at a temperature of from-30 ℃ to +50 ℃, in a solvent such as a halogenated hydrocarbon and/or an aromatic solvent, and optionally in the presence of an amine capable of binding an acid as described above.

A compound of the formula IV obtained by reaction of a compound of the formula II with a compound of the formula III, a protecting group R¹⁰¹、R²⁰¹And R³⁰²If they are not the desired groups capable of forming biolabile esters, can be cleaved in a manner known per se.

If desired, R in the compounds of the formula I¹、R²And R³For the same groups which form biolabile esters, it is then suitable to select the same protecting groups in the starting compounds of the formula II and in the starting compounds of the formula III. Suitably, the protecting group selected herein is also a group capable of forming a biolabile ester. If necessary to prepare R thereof¹、R²And R³Free acids of the formula I, each being hydrogen, then as protecting groups R¹⁰¹、R²⁰¹And R³⁰²The groups which are cleavable under the same conditions, preferably hydrogenolysis conditions, are each chosen. For example R¹⁰¹、R²⁰¹And R³⁰²Benzyl groups can be selected individually, which are simultaneously cleaved to the free acid groups under catalytic hydrogenation conditions. As catalysts for the catalytic hydrogenation, it is possible to use, for example, noble metal catalysts such as palladium on activated carbon. The reaction can be carried out in a solvent which is inert under the reaction conditions, for example in a lower alcohol such as ethanol, or in a lower alkyl ester such as ethyl acetate, or in a mixture of these solvents. It is suitable to carry out the catalytic hydrogenation at a hydrogen pressure of from 2 to 6 bar and at room temperature.

If it is desired to esterify the free phosphonic acid groups and/or free carboxylic acid groups of the compounds of the formula I, the free phosphonic acid groups of the compounds of the formula I can be reacted with the compounds of the formula Va or Vb in a manner known per se. The free carboxylic acid groups of the compounds of the formula I can be reacted with the compounds of the formula Vc in a manner known per se. As leaving group Y in the compounds of the formula Va, Vb or Vc there may be mentioned, for example, halogen, in particular chlorine or bromine, or the residue of a lower alkanol sulfonic acid, for example trifluoromethanesulfonyloxy, or the residue of an aromatic sulfonic acid, for example benzenesulfonic acid, or the residue of a benzenesulfonic acid, for example toluenesulfonic acid, substituted by lower alkyl or halogen.

If a compound of the formula I is prepared in which R is¹And R²Has the same meaning as R³Have different meanings, preferably, from R¹⁰¹And R²⁰¹Having the same meaningStarting with a starting compound of formula II, and from R³⁰²And R¹⁰¹And R²⁰¹Starting from starting compounds of the general formula III which differ in their meaning. For example, a phosphonic acid protecting group R which is stable under hydrogenolysis conditions can be selected¹⁰¹And R²⁰¹Such as lower alkyl, preferably ethyl. At the same time, as the carboxylic acid protecting group R³⁰²Groups cleavable under hydrogenolysis conditions, such as benzyl, may be used. Under the catalytic hydrogenation conditions, only benzyl group R is present in the obtained compound of the formula IV³⁰²Cleavage to free carboxylic acid, and ethyl R¹⁰¹And R²⁰¹Remain unchanged. The free carboxylic acid may then be esterified with a compound of formula Vc if desired. Likewise in the compounds of the formula I, a phosphonic acid protecting group R¹⁰¹And R²⁰¹R is a stabilizing group such as lower alkyl, preferably ethyl, under hydrogenation conditions³⁰²For the hydrocracked radicals, e.g. benzyl, the ethyl radical R is first reacted¹⁰¹And R²⁰¹By cleavage under acidic conditions, and benzyl R³⁰²Remain unchanged. If desired, the free phosphonic acid group can then be esterified with a compound of the formula Va or Vb, for example with pivaloyloxychloride. The benzyl radical R which can be cleaved under hydrogenation conditions can then be reacted³⁰²Cracking by catalytic reduction with hydrogen under conditions known per se to obtain R³A compound of formula I which is hydrogen.

If desired R¹And R²Compounds of the formula I having different meanings are preferably represented by R¹⁰¹And R²⁰¹Starting compounds of the general formula II having different meanings. For example, starting compounds of the formula II in which R is¹⁰¹Is hydrogen, R²⁰¹Is a phosphonic acid protecting group which is stable under hydrogenolysis conditions. For example R²⁰¹May be a lower alkyl group, preferably an ethyl group. If desired, the R obtained may be¹⁰¹The compound of formula I being hydrogen is then converted with a suitable compound of formula Va to obtain R¹And R²Compounds of formula I are different groups capable of forming biolabile esters. For example, from compounds of the general formula II, in which R¹⁰¹Is one under hydrogenolysis conditionThe radical which can be cleaved, for example benzyl, is subjected to catalytic hydrogenation under conditions known per se to give R¹⁰¹A starting compound of formula II which is hydrogen.

In the conversion reactions described above, the chiral carbon atom is not changed in the starting compounds of the formula III, so that, depending on the type of starting compound, isomerically pure compounds of the formula I or isomer mixtures can be obtained. To prepare a stereochemically pure compound of the formula I, it is appropriate to convert a stereochemically pure compound of the formula II with a stereochemically pure compound of the formula III. If a compound of the formula II which does not contain a chiral phosphine atom is reacted with a racemic compound of the formula III, a mixture of the two enantiomers of the compound of the formula I can be obtained. If desired, the mixture of enantiomers can be separated in a manner known per se, for example by chromatographic separation on chiral separation substances, or by conversion of a free carboxylic acid of the formula I with a suitable optically active base, for example with (-) - α -methyl-benzylamine, followed by separation of the optical enantiomers by fractional crystallization of the salts obtained.

The starting compounds of the formula II can be obtained in a manner known per se.

Thus, compounds of the formula II can be obtained in which compounds of the formula VI are reacted

Wherein R is¹⁰²And R²⁰²Respectively a phosphonic acid protecting group, Y having the above-mentioned meaning, with a cyclopentanecarboxylic acid of the formula VII,

if desired, the protective group R is then reacted in a manner known per se¹⁰²And/or R²⁰²Heavy and cracked. For example, compounds of the formula VI may be usedWherein Y is the residue of a lower alkanesulfonic acid, preferably trifluoromethanesulfonyloxy.

This reaction can be carried out in a manner known per se by reacting cyclopentanecarboxylic acid with a strong base which forms the dianion of cyclopentanecarboxylic acid, followed by conversion with the phosphonate derivative of the formula VI, in an organic solvent which is inert under the reaction conditions, under nucleophilic substitution conditions. Suitable solvents are, for example, open-chain dialkyl ethers, such as diethyl ether, or cyclic ethers, such as THF. Suitable strong bases are, for example, non-nucleophilic organic alkali metal ammoniums, such as diisopropyllithium amide (═ LDA). Suitably, the cyclopentanecarboxylic acid is converted with two equivalents of LDA in THF, and the reaction mixture is then converted further with the compound of formula VI. The reaction temperature may be between-70 ℃ and 0 ℃.

The compounds of the formula VI can be obtained in a manner known per se, for example from phosphonic diesters of the formula VIII

Wherein R is¹⁰²And R²⁰²Having the above meaning, with a source of formaldehyde, for example with paraformaldehyde. Suitably, the reaction is carried out in the absence of a solvent and in the presence of a base which is soluble in the reaction mixture. As base, the non-nucleophilic bases specified above for the conversion of compounds of the formula II with compounds of the formula III can be used. It is suitable to carry out the reaction at a temperature of between 50 ℃ and 130 ℃, preferably between 80 ℃ and 120 ℃. If desired, the compound of the formula VI obtained in which Y is hydroxy can then be converted in a manner known per se into a compound of the formula VI in which Y is a cleavable leaving group.

The compounds of the general formula VIII are known or can be prepared according to known methods. For example, esterified phosphonic acid derivatives of the general formula VIII can be prepared with two different biologically labile groups, where the phosphonic diester of the general formula VIII, where R is¹⁰¹And R²⁰¹Each of the same groups, for example lower alkyl, is first cleaved in one of the two ester groups with a base, for example an alkali metal hydroxide, for example with sodium hydroxide, and the monoester obtained or a salt thereof is then converted with the corresponding compound of the formula Va or Vb. To accelerate the reaction, a suitable catalyst such as a tetra-lower alkyl ammonium salt, for example tetrabutylammonium hydroxide, may be added. Suitably, a suitable alkali metal halide such as an alkali metal iodide, for example sodium iodide, may also be added to accelerate the reaction process. The reaction may be carried out in a dipolar aprotic solvent such as a lower alkyl cyanide e.g. acetonitrile, in a lower aliphatic ether such as diethyl ether, THF or dioxane, in dimethylformamide (═ DMF), in dimethyl sulfoxide (═ DMSO), or in a mixture of these solvents. Suitable temperatures for this are between 0 ℃ and 80 ℃, preferably between 5 ℃ and 40 ℃.

The compounds of the general formula III are known from European patent application, publication No. 0733642 and can be prepared according to the methods described therein.

The compounds of the general formula I and their pharmacologically tolerated salts have advantageous pharmacological properties. In particular, these substances inhibit endothelin-converting enzyme (ECE) and endopeptidase (NEP) and have particularly advantageous effects on the treatment of cardiac insufficiency.

In the case of cardiac insufficiency, the cardiac drainage function is reduced by the disease, resulting in an increase in reflex peripheral vascular resistance. The increased afterload must therefore be overcome when the heart muscle pumps blood. This may further exacerbate the condition by causing an increase in cardiac load in the vicious cycle. In addition, peripheral resistance is also increased by the action of the vasoactive peptide endothelin. Endothelin is the most potent, currently known, autologous vasoconstrictor substance produced by the action of ECE enzymes from the precursor macro-endothelin.

In the case of cardiac insufficiency, the return of blood to the pulmonary circulation and the return of blood to the heart itself occur due to a decrease in the cardiac function of the blood discharge and an increase in the peripheral resistance. Whereby the wall tension of the heart muscle in the atrium and ventricle is increased. In this case, the heart acts like an endocrine organ, also secreting the peptide ANP (atrial natriuretic peptide) into the circulation. Since it has excellent vasodilating and natriuretic/diuretic effects, ANP can reduce not only peripheral resistance but also circulatory blood flow. The result is a significant reduction in pre-load and post-load. This is an intrinsic cardioprotective mechanism. This beneficial endogenous mechanism is limited because ANP has only a short half-life in plasma. The reason is that hormones are rapidly decomposed by NEP.

The compounds of the invention prevent endothelin production by inhibiting ECE activity and thus counteract the increase in peripheral resistance, with a consequent reduction in myocardial load. The substances according to the invention, by inhibiting NEP-activity, lead in addition to an increased ANP-level and a prolonged ANP action. These enhance the endogenous ANP-induced cardioprotective mechanisms. In particular, these substances have a high effect on ANP-induced diuretic/natriuretic activity.

NEP is involved not only in the breakdown of ANP but also in the breakdown of endothelin. Thus, simple inhibition of NEP results in an undesirable increase in endothelin levels in addition to the desired increase in ANP-levels. For this reason, it is now assumed that the combined action of ECE-and NEP-inhibition is particularly advantageous, since not only the decomposition of ANPs with natriuretic/diuretic action (NEP-inhibition) is prevented, but also the endothelin production (ECE-inhibition) is suppressed. This eliminates the concomitant side effects of NEP-inhibitors (elevated endothelin levels).

1. Determination of the minimum toxic dose

Rats of 250g body weight (age 5 to 6 weeks) were grouped into 10 groups and injected intravenously at a maximum dose of 215mg/kg of test substance (dissolved in 0.1n aqueous sodium hydroxide solution at pH 7.1). From the moment of injection of the drug, animals were carefully observed for 5 hours of clinically significant toxic symptoms. In addition, 2 observations were made daily until the end of a week. After one week, all animals were dissected and examined visually for all organs. If death or overt toxication symptoms are observed, additional rats are dosed incrementally less until no more toxic symptoms are observed. The lowest dose that causes death and significant toxic symptoms is taken as the minimum toxic dose. The test substance of preparation example 2 showed no significant symptoms of toxicity at an intravenous dose of 215 mg/kg.

2. NEP-inhibiting action of test substances in vitro

To confirm the inhibitory effect of the substances of the present invention on endopeptidase (═ NEP), the inhibitory effect of the substances on the hydrogenolysis of methionine-cerebrophenapeptide (Met-cerebrophenapeptide) due to the NEP enzyme activity was examined in an in vitro standard test. Where the IC is determined₅₀The value is taken as a measure of the substance inhibition. IC of enzyme inhibiting substance₅₀The value is the concentration of the substance at which 50% of the NEP enzyme activity is inhibited.

Test implementation

To carry out the test, test samples containing 10ng of purified NEP (e.c.3.4.24.11) and various doses of test substance and various incubation solutions of 20 μ M substrate (Met-cerebrofeptide) and 50mM tretinoin buffer (═ tris (hydroxymethyl) aminomethane/hydrochloric acid, ph7.4) were prepared, 100 μ l each.

For each test substance 6 different incubation solutions containing 3 different test substance concentrations were prepared for each double assay.

In each test, two control-incubation solutions were treated separately, one being an enzyme control containing no test substance, and the other being a substrate control containing neither enzyme nor test substance.

The incubation solution was incubated at 37 ℃ for 30 minutes in a shaking water bath. Here, the enzyme reaction was started 15 minutes after the addition of the substrate (Met-cerebrophenapeptide) and terminated by heating at 95 ℃ for 5 minutes at the end of the incubation time. The terminated incubation solution was then centrifuged at 12.000Xg for 3 minutes, and then the unconverted substrate concentration and the concentration of the hydrogenolysis products generated by the enzymatic reaction were determined in the residue. Therein, theThe remaining test samples were each separated by high pressure liquid chromatography on hydrophobic silica gel (═ HPLA), and the products of the enzymatic reaction and the unconverted material were determined photometrically at a wavelength of 205 nm. Using a composition containing Nucleosin as an inversion phase separation material^*HPLA separation was carried out on a C18, 5 μ column (4.6X 125 mm). The solvent flow was 1.0 ml/min and the column was heated to 40 ℃. Flow agent A was 5mM H₃PO₄pH 2.5, flow agent B acetonitrile + 1% mM H₃PO₄，pH2.5。

From the determined concentrations of hydrogenolysis products and unconverted substrate in the various test samples, the IC of the test substance is calculated in a manner known per se₅₀-a value. Preparation of test substances from example 2 IC for NEP-inhibition in the assay₅₀-value of 1.7nM, thus demonstrating a high potency NEP-inhibitor.

3. In vivo determination of diuretic/natriuretic activity of active agents in rats subjected to volume loading Influence of

In vivo activity was determined in volume loaded rats. In this test, a high filling pressure of the heart is caused by the perfusion of an isotonic sodium chloride solution, with the result that ANP-release and thus diuresis/natriuresis occur.

Test implementation

The test was performed in male Wistar rats weighing 200-400 g. A catheter was inserted into the right femoral artery under neuroleptic analgesia (fentanyl; Hypnorm *, Janssen, Inc. of manufacture) for background perfusion and perfusion with isotonic sodium chloride solution. After opening the abdominal cavity, a second catheter is inserted into the bladder and the ureters are ligated so that urine volume, natrium and potassium can be measured.

The abdominal cavity was re-closed and the animals were continuously perfused with sodium chloride solution (0.5ml/100g body weight) for the entire duration of the 2 hour experiment. After an equilibration period of 30 minutes, urine test samples were measured 3 times each every 10 minute period during the administration of the test substance. The preliminary value (i.e. "prodrug" -value) was determined to monitor the sustained urine flow in the test animals.

The solutions containing the test substances are then administered intravenously (bolus injection into the femoral vein) or orally (via the pharyngeal tube) to groups of 10 rats each. For both administration forms, the control group was each provided with placebo solution only, without active substance. After 5 minutes of intravenous injection and 120 minutes of oral administration, rats were loaded (at a dose of 2ml/100g body weight over 2 minutes) with increasing volumes of sodium chloride solution intravenously and urine was collected over a period of 60 minutes. The amount of urine released and the sodium and potassium content contained therein were determined over this period of time. The increase in urination occurring under volume load relative to the prior value can be read from the amount of urine deposited.

The increase in urine output, expressed in%, that occurs under the volume load after administration of the test substance and the urine output that occurs under the volume load after administration of placebo are illustrated in the following tables. Sodium and potassium excretion, expressed as% under volume load, after administration of the test substance and sodium and potassium excretion under volume load after administration of placebo were also determined. The example numbers in tables 1 and 2 are for subsequent preparative runs.

TABLE 1

Test substance example No.	The administration mode is expressed in the dosage of mu Mol/kg	The increase in urine output after administration of the test substance under volume load is expressed in%, based on the amount of urine output after administration of placebo under volume load	The excretion of sodium and potassium under volume load after administration of the test substance is expressed in%, based on the excretion of sodium and potassium under volume load after administration of placebo Na K
					2	6.0i.v.20.0i.v.	117149	147246	116182
13	30.0p.o.	168	128	87
					22	30.0p.o.	127	161	106

4. In vivo examination of ECE-inhibiting action of active substance in rat

To demonstrate the inhibitory effect of the substances according to the invention on endothelin-converting enzyme (═ ECE), the inhibitory effect of the substances on the hydrogenolytic decomposition of large-endothelin (Big-ET) relative to endothelin (═ ET) which occurs as a result of the activity of the ECE enzymes was examined in standard in vivo tests. ET is a substance with a strong vasoconstrictive action in the body. Elevated ET-levels lead to elevated blood pressure. The extent of the increase in blood pressure upon infusion of Big-ET corresponds to that formed by ECE-catalytically cleaved ET. The inhibition of the increase in blood pressure due to the infusion of Big-ET by the substance was determined as a measure of the ECE-inhibition of the substance.

Test implementation

Male CD from Charles River Wiga with a weight of 220-^*Rats were tested. Under ketamine/xylazine-anesthesia, one catheter was inserted into the left jugular vein of the animal for administration and another catheter was inserted into the left carotid artery for blood pressure measurement. After a maintenance period of 30 minutes, the active substance solution is administered to the animals intravenously (i.v.) or intraduodenally (i.d.). After administration of the test substances, the animals were administered Big-ET intravenously at a dose of 0.5nmol/kg, respectively. The time intervals between administration of the test substances and administration of Big-ET were 5 minutes for intravenous administration, 15 minutes for administration of the test substances of examples 18 and 22 through the duodenum, and 30 minutes for administration of the test substances of examples 8 and 20 through the duodenum. Systolic and diastolic blood pressures were recorded every 5 minutes for the last 30 minutes. On untreated animals, a dramatic increase in blood pressure can be repeated by perfusion with 0.5nmol/kg of macro-endothelin for about 5 minutes.

In Table 2 below, the maximal increase in blood pressure after administration of Big-ET is illustrated in the control animals treated with placebo and in the animals treated with the test substance at various doses.

TABLE 2

Test substance example No.	Dosage by administration	Blood pressure is increased after Big-ET medication, and the systolic pressure and the diastolic pressure are expressed by mmHg
				Control 222 control 8182022	i.v.1mg/kg i.v.3mg/kg i.v.10mg/kg i.v.i.d.30μMol/kg i.d.30μMol/kg i.d.30μMol/kg i.d.30μMol/kg i.d.	653827-16125195036	3223140.44026173721

The above test results show that the compounds of the general formula I have a high affinity for ECE and NEP, and dose-dependently inhibit the ECE-activity of ET formation and the increase in peripheral vascular resistance and blood pressure caused thereby. The test results also show that these substances, in addition, promote an increase in the blood level of ANP and thus an increased diuretic/natriuretic effect by inhibiting ANP-lyase (NEP), without causing a substantial potassium loss.

Due to the effects explained above, the compounds of the general formula I are suitable as medicaments for higher mammals, especially humans, for the treatment of cardiac insufficiency and for promoting diuresis/natriuresis, especially in patients suffering from cardiac insufficiency. The compounds of the formula I and their salts and biologically labile esters are preferably used here in the form of pharmaceutical preparations for oral administration. The dosage to be employed may vary from individual to individual and will naturally vary depending on the disease state to be treated, the substance employed and the mode of administration. In general, the active substance content is from 1 to 200mg per unit dose in a pharmaceutical form suitable for administration to larger mammals, especially humans.

As a medicament, the compounds of formula I and usual pharmaceutical adjuvants may be contained in a gallon-wise formulation, for example in a tablet, capsule, suspension or solution. These gallon preparations can also be prepared in a manner known per se using customary solid or liquid carrier substances, for example lactose, starch or talc or liquid paraffin, and/or customary pharmaceutical adjuvants, for example tablet disintegrants, solvent adjustors or storage agents.

The following examples further illustrate the invention but are not intended to be limiting thereof.

The structure of the novel compounds is determined by spectroscopic examination, in particular by IR spectroscopy and optionally determination of optical rotation values.

Example 1: (3S) -3- (1-dibenzylphosphonomethyl-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester

A) 100ml dibenzyl phosphonite, 12.5g paraformaldehyde and 6.2ml triethylamine were added together with stirring. While heating slowly to 55 ℃, the temperature rose to 120 ℃. The now clear solution was cooled to 90 ℃ and stirred at this temperature for a further 30 minutes. After cooling to room temperature, chromatography over 1kg of silica gel under elevated pressure (eluent: n-hexane/ethyl acetate 1: 4). After concentrating the fractions and drying the residue at 60 ℃ for 12 hours under vacuum, 96.1g of pure, oily dibenzylhydroxymethyl phosphonate are obtained which can be reacted without further purification.

B) 17.8g dibenzylhydroxymethyl phosphonate are dissolved in 120ml dry dichloromethane. After cooling to-50 ℃, under the condition of moisture removal, firstly 7.3g of 2, 6-lutidine and then 10.6ml of trifluoromethanesulfonic anhydride are added dropwise in sequence. The reaction mixture was first stirred at-50 ℃ for 1 hour, then at 0 ℃ for another 1 hour. For the treatment, the mixture was poured into ice-cold water and the organic phase was washed first with diluted ice-cold hydrochloric acid and then with ice-cold water. The organic phase is dried over sodium sulfate and filtered, and concentrated by evaporation in vacuo. The crude product obtained is chromatographed on 200g of silica gel (eluent: n-hexane/ethyl acetate 3: 2). After concentration and drying of the product fraction, 17.0g of dibenzylphosphonomethyl trifluoromethanesulfonate were obtained as an oil.

C) 16.5ml of diisopropylamine are dissolved in 100ml of dry THF under nitrogen and with exclusion of moisture and cooled to-70 ℃. To the mixture was added dropwise a 1.6 molar solution of 65.5ml of n-butyllithium in n-hexane. Then stirred at 0 ℃ for 30 minutes, cooled to-20 ℃ and then at this temperature a solution of 5.3ml cyclopentanecarboxylic acid in 20ml THF is added dropwise. The reaction mixture was first stirred at-20 ℃ for 30 minutes, then at 0 ℃ for 2 hours, then cooled to-60 ℃. To this solution, a solution of 20.0g of the product obtained above under B) in 20ml of THF is slowly added dropwise. After the addition was complete, the mixture was stirred at-30 ℃ for 1 hour and then at-20 ℃ for 1 hour. The reaction mixture was poured into an ice-cooled aqueous potassium hydrogensulfate solution and extracted with methyl-tert-butyl ether (═ MTBE). The organic phase was separated, washed with saturated brine solution, dried over sodium sulfate and filtered and concentrated in vacuo. The crude product obtained is purified by chromatography on 300g of silica gel, eluting with pure MTBE in which a 5% to 10% rising methanol fraction is mixed. For further purification, the product thus obtained is chromatographed again on 200g of silica gel to give 6.7g of pure 1-dibenzylphosphonomethyl-1-cyclopentanecarboxylic acid having a melting point of 89-92 ℃.

D) A solution of 24.5g of racemic 3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester in 54ml of ethanol was heated to 65 ℃ and to this solution was added a solution of 12.65g of left- (+) -tartaric acid in 54ml of ethanol heated to 65 ℃. The mixture was stirred at room temperature for 1 hour. A solution of 1.72ml of benzaldehyde in 1.3ml of ethanol is then added dropwise. The suspension obtained is boiled under reflux at 80 ℃ for 14 hours and then cooled to room temperature. The crystalline precipitate formed is suction filtered, taken up in 80ml of ethanol and boiled again under reflux for 8 hours. Then cooled to room temperature, the crystals were suction filtered and dried under reduced pressure at 50 ℃. Obtaining 23.6g tartrate with a melting point of 195-196 ℃; [ alpha ] to]²⁰ _D-152.0 ° (c-0.5 in methanol).

E) To liberate the base, 23.6g of tartrate are cooled to 0 ℃ with stirring in a mixture of 250ml of water and 108ml of dichloromethane, and the pH is adjusted to 9.6 by adding aqueous ammonia solution. The organic phase is separated, the aqueous phase is extracted again with 30ml of dichloromethane, the organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining precipitate was crystallized from MTBE and dried under reduced pressure. 12.2g of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester are obtained, with a melting point of 113 ℃ and a melting temperature of [ alpha ] -, [ 115 ℃ ]]²⁰ _D-276.2 ° (c 0.5 in methanol).

F) 3.6g of the pure enantiomeric tert-butyl ester obtained above were added together with 2.8g of p-toluenesulfonic acid and 6.9ml of benzyl alcohol in 60ml of toluene. The mixture is then boiled in a water sedimentation tank for 3 hours, the toluene is filtered off with suction in vacuo and the residue is stirred with MTBE. After decanting the solvent, the residue was taken up in dichloromethane and shaken with ice-cold diluted aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water. The organic phase is then dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is crystallized from MTBE and dried. 3.2g of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester are obtained, with a melting point of 113 ℃, [ alpha ] -]²⁰ _D-236.8 ° (c 0.5 in methanol).

G) 5.8g of the acid obtained in C) above were taken up in 148ml of dry dichloromethane. To the solution obtained 4.8g of the product obtained above, 3.7ml of N-methylmorpholine, 1.84g of 1-hydroxybenzotriazole and 5.8g of 5.8g N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide-hydrochloride are added successively. The reaction mixture was then stirred at room temperature for 1 hour with exclusion of humidity. For workup, the reaction mixture is diluted with dichloromethane and washed successively with water, aqueous potassium hydrogen sulfate solution, water, aqueous sodium hydrogen carbonate solution and again with water. The organic phase is dried over sodium sulfate and evaporated in vacuo to give 10.5g of crude product which is purified by chromatography on 200g of silica gel (eluent: n-hexane/ethyl acetate 3: 7). After evaporation of the product fractions and drying in vacuo, 6.5g of pure product were isolatedThe title compound, as solid foam, IR: 3400, 3310, 2940, 1740, 1650cm^-1(film); [ alpha ] to]²⁰ _D-104.6 ° (c ═ 0.754 in methanol).

Example 2: (3S) -3- (1-phosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid

A) 1.9G of benzyl (3S) -3- (1-dibenzylphosphono-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see example 1G) were dissolved in 100ml of ethanol. To this was added 1.2g of a 5% palladium on activated carbon catalyst and the mixture was hydrogenated for 3 hours under a hydrogen pressure of 5.5 bar. For work-up, the catalyst is filtered, concentrated by evaporation in vacuo and dried. 0.9g of the title compound are obtained as a foamy product, IR: 3400, 1720, 1630cm^-1(KBr)；[α]²⁰ _D-140.8 ° (c-0.5 in methanol).

B) 701mg of the free acid obtained above and 238mg of sodium carbonate are dissolved in 60ml of water and the solution is concentrated by evaporation in vacuo. The residue obtained is taken up in MTBE and concentrated by evaporation in vacuo. The solid foam obtained now was crystallized from isopropanol, the crystals were separated from the solvent and dried at 60 ℃ in vacuo. 700mg of the sodium salt of the title compound are obtained, the melting point is more than 270 ℃; [ alpha ] to]²⁰ _D-159.7 ° (c ═ 0.149 in methanol).

Example 3: (3S) benzyl 3- (1-benzylethylphosphonomethyl-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate

A) A solution of 8.0g of sodium hydroxide in 30ml of water and 30ml of ethanol was added dropwise to 27.6g of diethyl phosphonite under ice-cooling, and stirred at room temperature for 2 hours. The concentration is then evaporated in vacuo and the aqueous residue is extracted 4 times with MTBE. The aqueous phase was evaporated in vacuo to give 25.0g of phosphonous acid ethyl sodium hydrogen salt as a white powder which was reacted without further purification.

B) In thatTo a solution of 33.9g of tetrabutylammonium hydrogen sulfate salt in 20ml of water was added a solution of 4.0g of sodium hydroxide in 22ml of water while maintaining the temperature at 25 ℃ under ice cooling. 12.5g of the product obtained above dissolved in 15ml of water are then added dropwise at room temperature. After stirring for 15 minutes, the precipitated sodium sulfate is filtered off with suction and the filtrate is extracted 4 times with 50ml of dichloromethane in each case. The combined organic phases are dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was dried in vacuo at 40 ℃ for 1 hour, dissolved in 120ml of anhydrous acetonitrile and then reacted with 7.07ml of benzyl bromide and 0.4g of sodium iodide. Stirring was carried out at 50 ℃ for 12 hours, the solvent was removed in vacuo and the residue was taken up in n-hexane. The solid residue is filtered off with suction, washed with a mixture of n-hexane and MTBE and dried. The resulting solution is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel (eluent: n-hexane/ethyl acetate 2: 3). 6.7g of benzylethyl phosphonite are obtained as an oil, IR: 2420, 1255, 970cm^-1(film).

C) 18.0g of the above product were converted with 2.5g of paraformaldehyde and 1.2ml of triethylamine in the manner described in example 1A). Chromatography over 200g of silica gel (eluent: ethyl acetate) gave 16.5g of benzylethylhydroxymethyl phosphonate as an oil, IR: 3300, 1230, 1030cm^-1(film).

D) 12.0g of the product obtained above were converted with 6.2g of 2, 6-lutidine and 9.0ml of trifluoromethanesulfonic anhydride in the manner described in example 1B). Chromatography over 200g of silica gel (eluent: n-hexane/ethyl acetate 2: 3) gave 16.3g of benzylethylphosphonomethyl trifluoromethanesulfonate as an oil, IR: 1410, 1245, 1210, 1010cm^-1(film).

E) The dianion of cyclopentanecarboxylic acid was prepared as described in example 1C) from 16.08ml of diisopropylamine, 63.8ml of a 1.6 molar solution of n-butyl-lithium in n-hexane, and 5.3ml of cyclopentanecarboxylic acid and converted in the manner described therein with 16.0g of the product obtained in D) above. The crude product is chromatographed on 300g of silica gel (eluent: n-hexane/ethyl acetate 1: 1 first, then gradually replaced by pure ethyl acetate) to give 7.1g of a pure oil1- (benzylethylphosphonomethyl) -1-cyclopentanecarboxylic acid, IR: 2950, 1720, 1210, 1175, 1010cm^-1(film).

F) 3.1G of the acid obtained above were converted with 3.2G of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-benzyl ester (cf. preparation example 1F)), 3.3ml of N-methylmorpholine, 1.35G of hydroxybenzotriazole and 3.8G of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide-hydrochloride following the procedure described in example 1G). Chromatography over 200g of silica gel (eluent: ethyl acetate) gave 2.3g of the title compound as a viscous oil, IR: 3410, 2940, 1735, 1660, 1230, 1020 cm^-1(KBr)；[α]²⁰ _D-121.6 ° (c ═ 0.495 in methanol).

Example 4: (3S) -3- (1-Benzylethylphosphonomethyl-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

A) 5.0g of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester (preparation cf. example 1E)) and 3.75g of p-toluenesulfonic acid are dissolved in 80ml of toluene and boiled in a water precipitation bath for 2.5 hours. A total of 200ml of ethanol are then added in portions and the resulting reaction mixture is digested under reflux for 3.5 hours. The mixture was then concentrated in vacuo and the residue taken up in dichloromethane. Then shaken with ice-cold sodium carbonate solution and the organic phase washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and the residue left to dry. 3.6g of ethyl (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate are obtained, the melting point is 106.5-108 ℃; IR 3350, 3300, 2930, 1735, 1660cm^-1(film); [ alpha ] to]²⁰ _D-288.4 ° (c 0.5 in methanol).

B) 3.1G of 1- (benzylethylphosphonomethyl) -1-cyclopentanecarboxylic acid (cf. preparation example 3E)) were reacted as described in example 1G) with 2.6G of the product obtained above, 3.3ml of N-methylmorpholine, 1.35G of hydroxybenzotriazole and 3.8G of 3.8G N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide-hydrochloride. Chromatography on 200g of silica gel (eluent: n-hexane/ethyl acetate 1: 1 first, then gradually changing to composition 3: 7) gave 3.7g of the title compound as an oil, IR: 3410, 2950, 1735, 1660cm^-1(film); [ alpha ] to]²⁰ _D-113.6 ° (c ═ 0.639 in methanol).

Example 5: (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

3.2g of ethyl (3S) -3- (1-benzylethylphosphonomethyl-cyclopentane-1-carbonyl-amino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (cf. example 4 for preparation) were mixed with 1.0g 5% palladium on charcoal catalyst and hydrogenated at 2.2 bar hydrogen pressure according to the method described in example 2). After work-up, 2.4g of the title compound are obtained as a foam resin, IR: 3400, 2950, 1740, 1650cm^-1(KBr)；[α]²⁰ _D-162.0 ° (c-0.324 in methanol).

Example 6: (3S) -3- [1- (pivaloyloxymethyl-ethylphosphonomethyl) -cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

0.6g of ethyl (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (cf. preparation example 5) are dissolved in 20ml of DMF at the exclusion of humidity and subsequently admixed with 1.86ml of triethylamine, 0.88ml of pivaloyloxymethyl chloride and 0.1g of dimethylaminopyridine. The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the residue was taken up in dichloromethane. The organic phase is washed with water and then dried over sodium sulfate. Concentration in vacuo afforded the crude product which was chromatographed over 50g of silica gel (eluent: first n-hexane/ethyl acetate 3: 7, then the ester content was gradually increased to 100%). 188mg of the title compound are obtained as an oil, IR 1740, 1650cm^-1(CH₂Cl₂)；[α]²⁰ _D-124.1 ° (c-0.228 in methanol).

Example 7: (3S) -3- [1- (5-2, 3-dihydroindenylethylphosphonomethyl) -cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

480mg of ethyl (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation cf. example 5) are dissolved in 10ml of dry dichloromethane and mixed with 0.28ml triethylamine. The solution was cooled to-50 ℃ and then 0.09ml of oxalyl chloride was added. Then mixed with 200mg of 2, 3-indan-5-ol (5-indanol) at-50 ℃ and heated to 0 ℃ and stirred at room temperature for a further 5 hours. The organic phase is washed with water, separated, dried over sodium sulfate and concentrated by evaporation under reduced pressure. Chromatography over 80g of silica gel (eluent: n-hexane/ethyl acetate 1: 1, solvent ratio gradually changing to 1: 4) and drying in vacuo afforded 220mg of the title compound as a viscous resin, IR: 1740, 1655cm^-1(CH₂Cl₂)；[α]²⁰ _D-135.1 ° (c ═ 0.205 in methanol).

Example 8: (3S) -3- (1-Benzylethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester

Following the procedure described in example 1G), 5.0G of 1- (benzylethylphosphonomethyl) -1-cyclopentanecarboxylic acid (preparation cf. example 3E)) were converted with 5.15G of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester (preparation cf. example 1E)), 4.1ml of N-methylmorpholine, 2.0G of hydroxybenzotriazole and 6.3.3 6.3G N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide-hydrochloride. The crude product obtained is chromatographed on 200g of silica gel (eluent: n-hexane/ethyl acetate 1: 1 first, then pure ethyl ester). 2.6g of the title compound are obtained as a foam resin, IR 3410, 3350, 1735, 1655cm^-1；[α]²⁰ _D-118.1 ° (c ═ 0.609 in methanol).

Example 9: (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester

A) 3.5g of 1- (benzylethylphosphonomethyl) -1-cyclopentanecarboxylic acid (cf. example 3E for preparation) are dissolved in 150ml of ethanol and admixed with 1.0g of 5% palladium on activated carbon catalyst. Then hydrogenated at a hydrogen pressure of 2.1 bar for 4 hours. The catalyst was filtered 2 times, evaporated in vacuo and dried in vacuo. 2.60g of 1-ethyl-phosphonomethyl-1-cyclopentanecarboxylic acid are obtained in the form of an oil which can be reacted without further purification.

B) The product obtained was dissolved in 100ml dichloromethane with exclusion of moisture, mixed with 3.5g carbonyldiimidazole and 3.56g (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-benzyl ester (preparation see example 1F)), and stirred overnight. Then poured onto saturated aqueous potassium hydrogen sulfate solution, the organic phase was washed with water neutral and dried overnight. The crude product obtained is chromatographed on 150g of silica gel (eluent: ethyl acetate first, dichloromethane is gradually mixed until the solvent ratio is 1: 1). After drying the product fractions in vacuo, 1.4g of the title compound are obtained as a solid foam, IR: 3410, 1740, 1645cm^-1(KBr)；[α]²⁰ _D-130.7 ° (c ═ 0.339 in methanol).

Example 10: (3S) benzyl 3- (1-diethylphosphonomethyl-1-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate

A) 69.05g of dimethyl phosphonite were converted with 14.5g of paraformaldehyde and 6.96ml of triethylamine by the method described in example 1A). 66.02g of diethylhydroxymethyl phosphonate are obtained which, after drying in vacuo, can be converted directly without purification.

B) 21.02g of the phosphonate obtained above, 15.0g of 2, 6-lutidine and 21.8ml of trifluoromethanesulfonic anhydride were converted in the manner described in example 1B). 32.5g of diethylphosphonomethyl trifluoromethanesulfonate were obtained as an oil.

C) 30.0g of the trifluoromethyl sulfonate obtained above were converted with 133ml of a 1.6 mol n-butyllithium solution in n-hexane and 10.8ml of cyclopentanecarboxylic acid by the method described in example 1C). To give 11.1g of diethylphosphonomethyl-1-cyclopentanecarboxylic acid, IR: 2970, 1730, 1240, 1030cm^-1(film).

D) 5.74G of the carboxylic acid derivative obtained above were converted with 7.05G of (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-benzyl ester (cf. example 1F for preparation)) according to the method described in example 1G). The crude product obtained is purified by chromatography on silica gel (eluent: ethyl acetate). 7.95g of the title compound are obtained, IR 3400, 1745, 1650cm^-1(film); [ alpha ] to]²⁰ _D-130.3 ° (c-0.538 in methanol).

Example 11: (3S) -3- (1-diethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid

5.3g of benzyl (3S) -3- (1-diethylphosphonomethyl-1-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see example 10) are dissolved in 250ml of ethanol, mixed with 1.5g of 5% palladium on activated carbon catalyst and hydrogenated as described in example 2. 4.3g of the title compound are obtained, IR 3390, 1730, 1650cm^-1(KBr)；[α]²⁰ _D-156.6 ° (c-0.514 in methanol).

Example 12: (3S) -3- (1-Diethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

2.34g of (3S) -3- (1-diethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid (preparation see example 11) are dissolved in dichloromethane at exclusion of humidity and reacted with 1.6ml of N-methylmorpholine, 0.63g of hydroxybenzotriazole, 2.0g ofN- (3-dimethylaminopropyl) -N' -ethylcarbodiimide-hydrochloride and 0.6ml ethanol were mixed and stirred at room temperature for 4 hours. The reaction mixture was then washed with water, potassium hydrogen sulfate solution, water, sodium bicarbonate solution and water in that order. The organic phase is then separated, dried over sodium sulfate and concentrated by evaporation in vacuo. The product formed is chromatographed on 200g of silica gel (eluent: initially ethyl acetate and then 5% methanol mixed addition), the product fractions are concentrated and dried in vacuo. 1.6g of the title compound are obtained, IR 3410, 1740, 1650, 1200, 1030cm^-1(film); [ alpha ] to]²⁰ _D-126.1 ° (c ═ 0.584 in methanol).

Example 13: (3S) -3- (1-phosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

1.3g of (3S) -3- (1-diethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester (preparation see example 12) were dissolved in 13ml of dry dichloromethane under a nitrogen atmosphere. 0.5ml of bromotrimethylsilane and 0.4ml of triethylamine were added under ice cooling, and stirred overnight. The excess solvent was filtered off with suction in vacuo and the residue was stirred in water-soluble acetone for 15 minutes. The residue remaining after evaporation of the solvent was taken up in MTBE to which a little dichloromethane was added and mixed with 0.53g of (S) - (-) - α -methylbenzylamine. The precipitated solid material was crystallized once from ethanol, while the title compound was obtained as α -methyl-benzylammonium salt with melting point 210-. 2940, 1750, 1650, 1200, 1045, cm^-1(KBr)；[α]²⁰ _D-141.0 ° (c-0.2 in methanol).

Example 14: (3S) -3- (1-phosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester

3.8g of benzyl (3S) -3- (1-diethylphosphonomethyl-1-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (for preparation see examples)10) Dissolved in 10ml of methylene chloride, and mixed with 10.3ml of trifluoroacetic acid under ice cooling, followed by stirring at room temperature for 18 hours. The solvent is filtered off with suction in vacuo, the residue remaining is taken up several times in toluene and concentrated again by evaporation each time. The crude product obtained is dissolved in dichloromethane and washed 3 times with water, the organic phase is then separated, dried over sodium sulfate and the solvent is concentrated by evaporation in vacuo. After drying in vacuo, 3.0g of the title compound were obtained as an oil, IR 3400, 2950, 1745, 1640cm^-1(KBr)；[α]²⁰ _D-146.5 ° (c ═ 0.2 in methanol).

Example 15: (3S) -3- (1-diisopropylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester

A) 50.0g of diisopropyl phosphonite, 8.5g of paraformaldehyde and 4.0ml of triethylamine are converted as described in example 1A). The crude product is chromatographed on silica gel (eluent: n-hexane/ethyl acetate 1: 4) to give 37.5g of diisopropylmethyl phosphonate as an oil which can be reacted without further purification.

B) 19.6g of the compound obtained above were converted with 17.4ml of trifluoromethanesulfonic anhydride and 11.96g of 2, 6-lutidine in the manner described in example 1B). The crude product is chromatographed on silica gel (eluent: n-hexane/ethyl acetate 3: 7) to give 37.4g of diisopropylphosphonomethyltrifluoromethylsulfonate as an oil, IR 2980, 1410, 1205, 1000cm^-1(film).

C) 27.4g of the compound obtained above, 10.05ml of cyclopentanecarboxylic acid and 120ml of a 1.6 molar solution of n-butyllithium in n-hexane were converted as described in example 1C). The crude product is chromatographed on silica gel (eluent: n-hexane/ethyl acetate 3: 7 first, the ethyl ester content is gradually increased to 100%) to give 10.6g of diisopropylphosphonomethyl-1-cyclopentanecarboxylic acid having a melting point of 53-57 ℃.

D) 2.05G of the compound obtained above were mixed with 2.24G of the compound obtained as described in example 1G)(3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-benzyl ester (preparation see example 1F)). 3.5g of the title compound are obtained in the form of an oil, IR-3410, 1735, 1650, 1240, 1180cm^-1(film); [ alpha ] to]²⁰ _D-127.5 ° (c-0.287 in methanol).

Example 16: (3S) -3- (1-Benzylpropylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester

A) 92.0ml of diisopropyl phosphonite and 22.2g of sodium hydroxide are converted according to the process described in example 3A). 88.0g of sodium isopropylhydride phosphonous acid are obtained, which can be converted directly without purification.

B) In analogy to the procedure described in example 3B), 88.0g of the compound obtained above and 34ml of benzyl bromide were converted. 46.3g of benzylisopropyl phosphonoate are obtained in the form of an oil which can be converted without further purification.

C) 46.3g of the compound obtained above were converted with 6.1g of paraformaldehyde and 2.87ml of triethylamine in the manner described in example 1A). 24.0g of benzylisopropylhydroxymethyl phosphonate are obtained as an oil, IR 3300, 1230, 995cm^-1(film).

D) 24.0g of the compound obtained above were converted with 18.01ml of trifluoromethanesulfonic anhydride and 13.57ml of 2, 6-lutidine in the manner described in example 1B). 32.5g of benzyl isopropyl phosphonomethyl trifluoromethanesulfonate as an oil, IR 2980, 1410, 1245, 1000cm^-1(film).

E) 32.5g of the compound obtained above, 9.65ml of cyclopentanecarboxylic acid and 13.4ml of a 1.6 molar solution of n-butyllithium in n-hexane were converted as described in example 1C). The crude product is chromatographed on silica gel (eluent: n-hexane/ethyl acetate 1: 1 first, then pure ethyl ester, then ethyl acetate with 5% by volume isopropanol) to give 7.0g of 1-benzyl isopropylphosphonomethyl-1-cyclopentanecarboxylic acid, which can be converted directly without purification.

F) 1.25G of the compound obtained above are converted with 1.06G of ethyl (3S) -3-amino-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (cf. example 4A for preparation) by the method described in example 1G). 0.68g of the title compound are obtained, IR: 2400, 1735, 1655, 1200, 985cm^-1(film); [ alpha ] to]²⁰ _D-123.0 ° (c ═ 0.1 in isopropanol).

Example 17: (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester

Following the procedure described in example 2, 2.2g of (3S) -3- (1-benzylethylphosphonomethyl) -cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester-tert-butyl ester (cf. example 8 for the preparation) were hydrogenated with 1.0g of 5% palladium on charcoal catalyst at 2.5 bar hydrogen pressure. 1.7g of the title compound are obtained, IR: 3400, 1735, 1650, cm^-1(film); [ alpha ] to]²⁰ _D-158.2 ° (c-0.515 in methanol).

Example 18: (3S) -3- [1- (pivaloyloxymethyl-ethylphosphonomethyl) -cyclopentane-1-carbonylamino]-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester

According to the method described in example 6, 0.6g of (3S) -3- (1-ethylphosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester (preparation see example 17) was converted with 1.73ml of triethylamine, 0.86ml of pivaloyloxymethyl chloride and 0.1g of dimethylaminopyridine. Chromatography over silica gel (eluent: ethyl acetate) gave 329mg of the title compound as a viscous resin, IR 1740, 1650cm^-1(CH₂Cl₂)；[α]²⁰ _D-122.9 ° (c ═ 0.257 in methanol).

Example 20(3S) -3- [ 1-phosphonomethyl-cyclopentane-1-carbonylamino) -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester: salt forms

A) 961mg of the above free phosphonic acid are mixed with 212mg of sodium carbonate and 20ml of water. The resulting mixture was filtered and the filtrate obtained was concentrated by evaporation in vacuo. The obtained residue was crystallized from ethanol, and the crystals were dried in vacuo at 60 ℃ for 1 day. 750mg of the sodium salt of the title compound are obtained, melting point > 270 ℃ and alpha]²⁰ _D-141.5 ° (c-0.25 in methanol).

B) 961mg of the free phosphonic acid described above are dissolved in 20ml of MTBE and mixed with 0.42ml of tert-butylamine. The resulting solution was concentrated by evaporation in vacuo and the residue obtained was taken up in a mixture of MTBE/n-hexane. The crystals formed in the solvent mixture were isolated and dried in vacuo at 60 ℃. 950mg of the ammonium salt of the title compound are obtained, with a melting point of 215-220 ℃; [ alpha ] to]²⁰ _D-149.8 ° (c ═ 0.26 in methanol).

The compounds of general formula I given in table 3 below can also be prepared according to the methods described in the preceding examples.

Table 3:

ET ═ ethyl;^tbu-t-butyl; POM ═ pivaloyloxymethyl; ind ═ 2, 3-indan-5-yl; bn ═ benzyl;ⁱpr ═ isopropyl group

Example I: containing (3S) -3- [1- (pivaloyloxymethyl-ethylphosphonomethyl) -cyclopentane-1-carbonylamino]-2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester capsule

The capsule is prepared according to the following components contained in each capsule:

(3S) -3- [1- (pivaloyloxymethyl-ethylphosphonomethyl)

Cyclopentane-1-carbonylamino ] -2, 3, 4, 5-

tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid-tert-butyl ester 20mg

Corn starch 60mg

Lactose 301mg

Ethyl acetate q.s.

The active substance, corn starch and lactose are processed with the aid of ethyl acetate to form a homogeneous, pasty mixture. The paste was crushed and the granules formed were placed on a suitable metal plate and dried at 45 ℃ to remove the solvent. The dried granules were passed through a pulverizer and then mixed in a mixer with the following other adjuvants:

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into capsules, which may contain 400 mg.

Claims (4)

1. Physiologically tolerated salts of compounds of the general formula I and acids of the general formula I,

wherein

R¹Hydrogen, or a group capable of forming a biologically labile phosphonate,

R²hydrogen, or a group capable of forming a biologically labile phosphonate,

R³is hydrogen, or an organism capable of generatingThe group of labile carboxylic esters.

2. A compound according to claim 1, wherein R is³Is hydrogen or lower alkyl.

3. A medicament containing a pharmacologically effective amount of a compound according to claim 1 and customary pharmaceutical adjuvants and/or carrier substances.

4. A process for the preparation of compounds of the general formula I and physiologically tolerated salts of acids of the general formula I

Wherein

R¹Hydrogen, or a group capable of forming a biologically labile phosphonate,

R²hydrogen, or a group capable of forming a biologically labile phosphonate,

R³hydrogen, or a group capable of forming a biologically labile carboxylate,

it is characterized in that,

a) to prepare compounds of the formula IV

Wherein R is¹⁰¹And R²⁰¹Each independently of the others being hydrogen or a phosphonic acid protecting group, R³⁰²For a carboxylic acid protecting group, a compound of formula II

Wherein R is¹⁰¹And R²⁰¹Having the above-mentioned meaning, with a compound of the general formula III,

wherein R is³⁰²Has the advantages ofThe above meanings, and, if R¹⁰¹And/or R²⁰¹The free phosphonic acid function is optionally esterified for hydrogen by means of compounds of the formula Va and/or Vb,

R¹¹⁰-Y(Va) R²¹⁰-Y(Vb)

wherein R is¹¹⁰And R²¹⁰Each being a group capable of forming a biologically labile phosphonate ester, Y being a hydroxyl group or a cleavable leaving group, being a biologically labile phosphonate ester group

b) If in the compounds of the formula IV the protecting group R¹⁰¹、R²⁰¹And/or R³⁰²Not the desired groups capable of forming biolabile esters, they are then cleaved simultaneously or separately in any desired sequence

Optionally, each free acid function is then converted into a biologically labile ester group by esterification of the free phosphonic acid function with a compound of the formula Va or Vb and/or by esterification of the free carboxylic acid function with a compound of the formula Vc,

R³¹⁰-Y (Vc)

wherein R is³¹⁰Is a group which forms a biologically labile carboxylate, Y has the meaning indicated above, and optionally the acid of the formula I is converted into a physiologically tolerable salt or the salt of the acid of the formula I is converted into the free compound.