Derivative benzazepine-n-acetic acid, substituted phosphonic acid, method of their preparation and medicines containing these compounds

 

The invention relates to new derivatives of benzazepine-N-acetic acid, substituted phosphonic acid, which are pharmaceutically active compounds. Describes derivatives of benzazepine-N-acetic acid, substituted phosphonic acid of the General formula Iwhere R1, R2, R3mean hydrogen or a group forming biolabeling ester phosphonic acid, and physiologically acceptable salts of the acids of formula I. Also describes the drug, possessing inhibiting neutral endopeptidase action, which includes a compound of formula (I) and the method of obtaining compounds of formula (I). The technical result - the creation of new pharmaceutically active substances. 3 c. and 1 C.p. f-crystals, 3 tables.

The present invention relates to new derivatives of benzazepine-N-acetic acid, which is substituted in position 3 cyclopentanecarbonitrile balance, bearing in position 1 the remainder of methylphosphonic acid, their salts and biolabeling esters, as well as containing these compounds, pharmaceutical preparations and methods of obtaining these compounds.

From European patent application, nome the surrounding inhibitory effect on neutral endopeptidase (NEP).

The objective of the invention is the creation of a new NEP-inhibitory effect, pharmaceutical active substances with a favorable profile of actions for the treatment of heart failure and high blood pressure.

It was found that new derivatives of benzazepine-N-acetic acid, substituted in position 3 of the frame of benzazepine cyclopentanecarbonitrile balance, bearing in position 1 the remainder of methylphosphonic acid, according to the invention possess valuable effective for heart pharmacological properties and are favorable profile of actions for the treatment of cardiovascular diseases, in particular heart failure, characterized by a combination of explicit inhibitory effect on neutral endo-peptidase with inhibitory action on the enzyme conversion of endothelin (ECE) and good compatibility.

The subject invention are new compounds of General formula Iwhere R1means hydrogen or a group forming biolabeling ester phosphonic acid, R2means hydrogen or a group forming biolabeling ester phosphonic acid, R3means hydrogen or a group forming by obtain these compounds and containing specified compound medicines.

The compounds of formula I are, if necessary, an acid derivatives containing groups, carboxylic and phosphonic acids, esterified forming biolabels esters groups. Biolabels esters of formula I are prodrugs of the free acids. Depending on the form of application are preferred biolabels esters or acids, the latter is suitable in particular for intravenous administration.

As groups, R1and R2forming biolabels esters of phosphonic acid, suitable groups that can be chipped off under physiological conditions in vivo with the allocation of appropriate functions phosphonic acid. So, for example, suitable lower alkyl groups, if necessary, With2-C6-alkanolamine group or phenyl, or phenyl-lower-accelgroup, the phenyl ring of which is optionally substituted one or more times lower alkyl, lower CNS radical or connected via two adjacent carbon atoms of the lower alkalinous chain. If the forming biolabeling ester group, R1and/or R2means or contains lower alkyl, sup> and/or R2represents, if necessary, replaced alkanoyloxy group, the latter may contain preferably branched alkanoyloxy from 2-6, preferably 3-5, carbon atoms and may mean, for example, pivaloyloxymethyl balance (tert-butylcarbamoyl balance). If R1and/or R2represent optionally substituted phenyl-lower-accelgroup, this group may contain alkylenes chain with 1 to 3, preferably 1, carbon atoms. If the phenyl ring is substituted chain lower Akilov, the latter may contain 3-4, preferably 3, carbon atoms, substituted phenyl ring is, in particular, indayla.

As groups, R3forming biolabels esters of carboxylic acids, suitable groups that can be chipped off under physiological conditions in vivo emitting carboxylic acid. So, for example, suitable lower alkyl groups, if necessary, phenyl or phenyl-lower-accelgroup, if necessary, substituted phenyl ring one or more times lower alkyl or lower CNS radical or connected via two adjacent carbon atom shim the alkyl dioxyalkylene group or, if necessary, replaced in oximately the group lower alkyl, C2-C6-alkanoyloxy group. If the forming biolabeling ester group, R3means or contains lower alkyl, the latter may be branched or unbranched and can contain from 1 to 4 carbon atoms. If the forming biolabeling ester group are optionally substituted phenyl-lower-accelgroup, this group may contain alkylenes chain with 1 to 3, preferably 1, carbon atoms and means mainly benzyl.

If the phenyl ring is substituted chain lower alkylene, the latter may contain 3-4, preferably 3, carbon atoms. If R3represents a substituted, if necessary, alkanolammonium group, the latter may contain predominantly branched alkanoyloxy from 2-6, preferably 3-5, carbon atoms and may be, for example, pivaloyloxymethyl balance.

According to the invention the new compounds of formula I and their salts get in a known manner, in which (a) to obtain compounds of General formula IV
where R101and R201independently from each other, eskers,
compounds of General formula II

where R101and R201have the above values,
enter into an interaction with compounds of General formula III

where R302has the above value,
and if R101and/or R201mean hydrogen transfer free function (available options) phosphonic acid, if necessary, by esterification with a compound of General formula Va and/or Vb
R110-Y (Va), R210-Y (Vb),
where R110and R210correspondingly represent a group forming biolabeling ester phosphonic acid, Y represents a hydroxyl radical or tsepliaeva volatile group,
in biolabeling broadcasting group, phosphonic acid,
b) if in the compounds of formula IV protective group, R101, R201and/or R302are not desired groups forming biolabeling ester, their otscheplaut simultaneously or separately one after another in any sequence and, if desired, transfer the appropriate released acid functions in biolabeling ester group, Emeryville when available functions phosphonic acid compound of the formula Va or Vb, and/or the AET group, forming biolabeling ester of carboxylic acid, and Y has the above meaning,
and, if necessary, the acid of formula I is transferred to their physiologically tolerated salt or salts of the acids of formula I into the free compound.

As physiologically-tolerated salts of the acids of formula I can be used according to their alkali metal salts, alkaline earth metals and ammonium, for example sodium, potassium or calcium, or salts with physiologically compatible pharmacologically neutral organic amines, such as, for example, diethylamine, tert-butylamine, or phenyl-lower-alkylamines followed, such as-methylbenzylamine.

As the protective groups R101and R201phosphonic acid can be selected for protection functions phosphonic acid customary protective groups, which are then again hatshepsuts known in itself by the way. As a protective group of carboxylic acid R302can be chosen for protection functions carboxylic acid customary protective groups, which can then be chipped off known in itself by the way. Acceptable protective group for carboxylic acids are known, for example, McOmie, "Protective Groups in Organic Chemistry" (Protective groups the science Publication. Acceptable protective group for the phosphonic acids are known, for example from Houben, Weyl "Methods der Organischen Chemie" (Methods of organic chemistry), published by G. Thieme Verlag, Stuttgart, new York, 1982 , pp. 313-341, and M. Kluba, A. Zwierak "Synthesis", 1978, pages 134-137, and McOmie, "Protective Groups in Organic Chemistry", Plenum Press. As the acid protective groups can also be applied to groups forming biolabeling ester. The compounds of formula IV obtained in the result of interaction between the compounds of formulas II and III, are already esters of the formula I according to the invention.

According to the invention as the protective groups R101and R201phosphonic acids are suitable such groups, which in an appropriate manner, independently from each other and independently of the likely presence of a protective group, R302carboxylic acid in the molecule can be split or selectively introduced. The protective group of the phosphonic acid can easily be chipped off by trimethylsilylpropyne selectively in the presence of a protective group of carboxylic acid. As examples tseplyaesh in various conditions protective groups, phosphonic acid, which can act as groups, forming biolabels esters FOS is t easily chipped off, for example, acids such as triperoxonane acid, and if both functions phosphonic acid tarifitsirovana groups lower unbranched Akilov, in terms of use of the base may be chipped off only one of these alkyl groups; branched lower alkali, such as tert-butyl, which can be easily derived with the use of acid, for example triperoxonane acid; substituted, if necessary, in the phenyl ring phenylmethylene groups such as benzyl, can easily be chipped off in destructive hydrogenation; alkanoyloxy groups, such as pivaloyloxymethyl, which can easily be chipped off, for example, acids such as triperoxonane acid; phenylmethylene group, such as p-methoxybenzyl, which substituted in the phenyl ring one or more times lower CNS radical and which under oxidizing conditions, for example, under the action of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (DDQ) or nitrite ammonium cerium (CAN) can be chipped off relatively easy.

As the protective groups R302carboxylic acids are suitable such groups that regardless of the likely presence of protective groups, phosphonic acid m the protective group of carboxylic acid, which can act as groups, forming biolabels esters of carboxylic acids include the following: unbranched lower alkali, such as ethyl, which can relatively easily be chipped off with the use of reason; branched lower alkali, such as tert-butyl, which can be easily derived acids such as triperoxonane acid; substituted, if necessary, in the phenyl ring phenylmethylene groups such as benzyl, can easily be chipped off in destructive hydrogenation or the use of reason; phenylmethylene group, such as p-methoxybenzyl, which is substituted in the phenyl ring one or more times lower CNS radical and which under oxidizing conditions, for example, under the influence of DDQ or CAN can be chipped off relatively easy.

The compounds of formula I contain a chiral carbon atom, namely the carbon atom in position 3 patterns benzazepine bearing amide side chain. Therefore, the compounds can exist in two optically active stereoisomeric forms or as racemic mixtures. The present invention includes both the racemic mixture and chitosamine saadatnia values, the phosphorus atom in the group of phosphonic acid may be chiral. Formed chiral phosphorus atoms of the isomeric mixture and chitosamine the compounds of formula I are also the subject of this invention.

The interaction of the acids of formula II with amines of the formula III with the formation of the amides of formula IV can be carried out by methods conventional in the formation of amide groups by aminoacylation. As a means of acylation can be applied carboxylic acid of the formula II or their reactive derivatives. Reactive derivatives can serve, in particular, mixed acid anhydrides and acid halides. So, for example, can be used anhydrides or bromohydrin acids of the formula II or mixed esters of the acids of formula II together with organic sulfonic acids, for example nitroalkane a sulfonic acids, substituted, if necessary, by halogen, such as methanesulfonate or triftoratsetata, or together with aromatic sulfonic acids, such as, for example, benzosulfimide, or substituted with lower alkyl or halogen-benzosulfimide, such as toluensulfonate or bromobenzonitrile. The acylation mo is anatoy. As suitable solvents, halogenated hydrocarbons such as dichloromethane, or an aromatic hydrocarbon such as benzene or toluene, or cyclic ethers, such as tetrahydrofuran (THF) or dioxane, or mixtures of these solvents.

It is advisable to carry out the acylation in particular, if Alliluyeva means is a mixed anhydride of the acid of formula II with one of the sulfonic acids in the presence of a reagent capable of binding acid. As acid binding substances are suitable, for example, soluble in the reaction mixture of organic bases, such as tertiary nitrogen base, such as tert-discalculia amines and pyridine, such as, for example, triethylamine, Tripropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 4-diethylaminophenyl or 4-pyrrolidinedione. Used in excess of an organic base can simultaneously serve as solvents.

When as a means of acylation are themselves acids of the formula II, the interaction of amine compounds of formula III with a carboxylic acid of formula II should be carried out in the presence of binding reagent, known from the chemistry of peptides as when the amides with the free acid in they react with the acid in natural conditions with the formation of a reactive derivative of the acid, it should, in particular, to call alkylhalogenide, such as cycloalkylcarbonyl, such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, carbonyldiimidazole and salts of N-nitroalkenes-2-halogenopyrimidines, in particular halides or toluensulfonate. Interaction in the presence of a binding reagent is expediently carried out at temperatures from -30 to +50oWith solvents, such as halogenated hydrocarbons and/or aromatic solvents and, if necessary, in the presence of the above-described linking acid amine.

Of the compounds of formula IV obtained by the interaction between the compounds of formula II and compounds of formula III, can be split in a known manner protective group, R101, R201and R302provided that they are not desired groups forming biolabeling ester.

In the case when you want to obtain the compounds of formula I in which R1, R2and R3mean identical groups forming biolabeling ester, it is advisable to choose identical protective group in the source soorya are both groups, forming biolabeling ester. If you want to get a free acid of formula I in which R1, R2and R3mean respectively hydrogen, as the protective groups R101, R201and R302can be selected, ceteris paribus, mainly in the destructive hydrogenation otsepleniya group. For example, for R101, R201and R302can be chosen benzyl group, which under conditions of catalytic hydrogenation can split with the formation of free acid groups. As catalysts for the catalytic hydrogenation can be used, for example, precious metals such as palladium on a carrier of activated charcoal. The reaction may be conducted in inert under the reaction conditions solvent, for example a lower alcohol, such as ethanol, or a lower alkyl ether complex, such as complex ethyl ester acetic acid, or in mixtures of these solvents. It is advisable to carry out catalytic hydrogenation under hydrogen pressure of 2 to 6 bar and at room temperature.

When you want etherification of the free phosphonic acid groups and/or free carbon groups who W ill result in an interaction with compounds of the formula Va or Vb is known in itself by the way. The free carboxylic acid group in the compounds of the formula I can in a known manner to enter into an interaction with compounds of formula Vc. As volatile group Y in the compounds of formulas Va, Vb, and Vc are suitable, for example, halogen, in particular chlorine or bromine, or the remains of the lower alkanovykh sulphonic acids, such as, for example, triftormetilfullerenov residue, or aromatic sulphonic acids, such as benzosulfimide, or benzosulphate slot, substituted lower alkyl or halogen, such as toluenesulfonic acid.

In the case when you want to obtain the compounds of formula I in which R1and R2have the same value, but different from R3should be starting compound of formula II in which R101and R201have identical values, as well as the parent compound of formula III in which R302has a value that differs from the R101and R201. For example, when gidroenergetichesky conditions can be selected protective group, R101and R201phosphonic acid, such as lower alkyl, preferably ethyl. At the same time as a protective group of carboxylic acid R302can be applied group, tsepliaeva when hydrogeol be chipped off from the obtained compounds of formula IV with a free carboxylic acid benzyl only group R302whereas ethyl group, R101and R201will remain intact. If desired, in conclusion, we can atrificial free carboxylic acid with a compound of formula Vc. Similarly, in the compounds of formula I, where the protective group R101and R201phosphonic acid at gidroenergetichesky conditions mean stable groups, such as groups of the lower Akilov, mainly ethyl, and R302means the group tsepliaeva hydrogenations, such as benzyl group, can be chipped off in the acidic conditions of the first ethyl group, R101, R201while retaining benzyl group, R302. If desired, in conclusion, we can atrificial free group phosphonic acid compounds of formulas Va and Vb, for example pivaloyloxymethyl. After that, benzyl group, R302, tsepliaeva when gidroenergetichesky conditions, can be split by catalytic regeneration using hydrogen in known conditions in order to obtain compounds of the formula I, in which R3means hydrogen.

If you want to obtain the compounds of formula I, where R1and R2have different values, then it is advisable to use the original compounds of formula II, where R101and R201 101 means hydrogen, R201- stable protective group of the phosphonic acid in gidroenergetichesky conditions. For example, R201can mean lower alkyl, preferably ethyl. If desired, the compounds of the formula I, in which R101means hydrogen, can then be entered into interaction with the corresponding compounds of formula Va with the aim of producing compounds of the formula I, where R1and R2do the different groups forming biolabeling ester. The initial compounds of the formula II in which R101means hydrogen, can be obtained, for example, from compounds of the formula II in which R101means the group tsepliaeva when gidroenergetichesky conditions, such as benzyl, by catalytic hydrogenation in known conditions.

Under the above reactions interaction of chiral carbon atoms do not undergo changes in the source compounds of the formula III, so depending on the type of raw materials it is possible to get pure isomeric compounds of formula I or an isomer mixture. To obtain a single stereochemical compounds of formula I it is advisable to enter into interaction stereochemical single compounds of formula II with a single stereochemical the interaction with the racemic compound of formula III, you get a mixture of the two enantiomers of the compounds of formula I. If desired, the mixture of antimirov can be divided in a known manner, for example, by chromatography on chiral separating materials or by the interaction of the free carboxylic acid of formula I with the appropriate optically active bases, such as (-)--methylbenzylamino, and subsequent separation of the optical antipodes fractionated crystallization of salts obtained.

The initial compounds of formula II can be obtained by known methods.

Thus can be obtained, for example, the compounds of formula II, for which compounds of General formula VI

where R102and R202mean respectively a protective group, phosphonic acid, Y has the above meaning,
enter into interaction with cyclopentanecarbonyl acid of the formula VII

then, if desired, again otscheplaut protective group, R102and/or R202using the known method. For example, there can be used compounds of the formula VI in which Y means the remainder of the lower alkanesulfonyl, preferably triforma-consultonline tion under the reaction conditions an organic solvent as a result of interaction cyclopentanecarbonyl acid with a strong base, capable to form dianion cyclopentanecarbonyl acid, with subsequent interaction with the derived ester of phosphonic acid of the formula VI. As suitable solvents, for example, dialkyl ethers with an open circuit, such as diethyl ether, or cyclic ethers, such as tetrahydrofuran (THF). As strong bases are suitable, for example, dinucleophiles organic amides of alkali metals, such as sitedisability (LDA). It is advisable to expose the interaction cyclopentanecarbonyl acid in THF with two equivalent amounts of LDA, then the reaction mixture is optionally enter into interaction with the compound of the formula VI. The reaction temperature may range from -70 to 0oC.

The compounds of formula VI can be obtained is known in itself by the way, for example by interaction of diesters of phosphonic acids of General formula VIII

where R102and R202have the above values,
with a source of formaldehyde, for example, paraformaldehyde. It is advisable to carry out the reaction without solvent, but when the part soluble in the reaction mixture grounds. As grounds may apply dinucleophiles grounds that brasno, to the reaction was carried out at a temperature of from 50 to 130oC, preferably from 80 to 120oC. the compounds of formula VI in which Y represents a hydroxyl radical, if desired, can be translated in a known manner into compounds of the formula VI in which Y will mean flying tsepliaeva group.

The compounds of formula VIII are known or can be obtained by known methods. For example, it is possible to obtain derivatives of phosphonic acid of the formula VIII, esterified two different violability groups, which from diesters of phosphonic acids of General formula VIII, in which R101and R201mean the same group, for example lower alkyl, otscheplaut under the action of bases, such as alkali metal hydroxide, for example sodium hydroxide, a first one of the two groups of ester, and the resulting complex monoether or its salt is introduced then in interaction with the corresponding compound of formula Va or Vb. To accelerate the progress of the reaction can enter the appropriate catalysts, such as salts of Tetra-lower-alkylamine, for example, tetrabutylammonium hydroxide. It is advisable to add to the reaction mixture the corresponding halides of alkali metals, such as alkaline iodides m is Eskom solvent, such as lower alkyl cyanide, for example acetonitrile, lower aliphatic ether, such as diethylether, THF or dioxane, dimethylformamide (DMF), dimethylsulfoxide (DMSO) or mixtures of these solvents. The necessary temperature range from 0 to 80oWith, preferably from 5 to 40oC.

The compounds of formula III are known from European patent application, publication number 0733642, and can be obtained uncovered in her methods.

The compounds of formula I and their pharmacologically acceptable salts are characterized by interesting pharmacological properties. In particular, substances slow down the action of the enzyme conversion of endothelin (ECE) and neutral endopeptidase (NEP) and are, therefore, especially advantageous profile of action for treatment of heart failure.

In heart failure caused by a disease reduction of his throwing ability leads to a reflex increase in peripheral resistance vessels. As a result, the myocardium has to overcome additional increased load. This creates a vicious circle that leads to increased load on the heart and additionally aggravates the condition. The increase in peripheral resistance dreams, currently known soudatsusen substance and is formed from predstavi big-endothelin under the action of the enzyme conversion of endothelin (ECE).

In diseases associated with heart failure, because of the reduced throwing ability of the heart and improve the resistance of the peripheral vessels occur the phenomenon of retrograde blood stasis in the pulmonary circulation and the heart. The result is an increase in the voltage of the wall of the myocardium in the area of the Atria and cameras. In this situation, the heart functions as an endocrine organ and secretes, among other things, the peptide ANP (trially peptide natriyureza) into the blood stream. Thanks to its pronounced activity against the expansion of blood vessels, natriyureza and diuresis ANP causes decrease as the resistance of the peripheral vessels and circulating blood volume. The result is a marked reduction in the initial and additional loads. It is an endogenous mechanism to protect the heart. Such positive endogenous mechanism is limited by the fact that ANP has only a very short half-life within the plasma. The reason for this is very rapid decomposition of the hormone neutral endo is knowing endothelin and thus counteract the increase in the resistance of the peripheral vessels, that has the effect of unloading of the heart muscle. The substances according to the invention cause, in addition, as a result of a slowdown in activity NEP increased level of ANP and increase the duration of its effect. This leads to increased action, providing ANP, endogenous cardioboxing mechanism. In particular, the compounds have a high efficiency for greater diuretichesky/natriuretic ANP-inducing activity.

Neutral endopeptidase (NEP) is involved not only in the decomposition trialing of peptide natriuresis (ANP), but also in the destruction of endothelin. It follows that the mere suppression of neutral endopeptidase (NEP) would, along with the required higher level trialing peptide natriyureza (ANP) and to undesirable increased levels of endothelin. For this reason, should be considered especially optimal mixed profile, which consists in suppressing the enzyme conversion of endothelin (ECE) and neutral endopeptidase as obstructed destruction trialing peptide natriyureza/diuresis (blockade neutral peptidases), and at the same time slows down the formation of endothelin (suppression of enzyme conversion of endothelin). Thereby no longer Prawna endothelin).

1.Determination of the minimum toxic dose.

Groups each of 10 rats with a body weight of 250 g (aged 5 to 6 weeks) intravenously was administered the test substance at the maximum dose 250 mg/kg (dissolved in 0.1 N. aqueous solution of NaOH, pH of 7.1). The animals were monitored closely since the introduction of substances for 5 hours on the manifestation of clinical signs of toxicity. In addition, during one week watched them twice a day. After a week performed a complete autopsy of each animal separately and macroscopically examined all the authorities. If it was mentioned death or severe toxic symptoms, then later the rats were injected substantially smaller doses until then, until he disappeared symptoms of toxicity. The lowest dose at which death occurred or manifested severe symptoms of toxicity, defined as the minimum toxic dose. The test substance obtained in example 2 and injected intravenously in the amount of 215 mg/kg, found no significant signs of toxicity.

2. The study of substances in vitro inhibitory effects of NEP - neutral endopeptidase.

To confirm the inhibitory action of the substances according to the invention in the neutral endopeptidase (Jonas-enkefalina (meth-enkephalin) by affecting the enzymatic activity of neutral endopeptidase. As the unit inhibiting the effectiveness of the substances was determined their value IC50. The value of the IC50the test substance with the effect of inhibition of the enzyme is the concentration of test substance at which blocked 50% of the enzymatic activity of neutral endopeptidase (NEP).

The test
The test samples were prepared in 100 μl of different incubation solutions each with a content of 10 nano-grams of purified neutral endopeptidase (E. C. 3.4.24.11) and, accordingly, different amounts of a test substance, and 20 μm of substrate (met-enkefalina) and 50 mm Tris buffer (Tris(hydroxymethyl)aminomethane/HCl, pH 7.4).

For each test substance was prepared 6 different incubation solutions with 3 different concentrations of this substance for a twofold definition.

During each test, respectively, were treated twice and the control incubation solutions, first, the control was performed with the enzyme without test substance, and, secondly, the control substrate, which is not contained neither the enzyme nor the test substance.

The incubation solutions were incubated for 30 minutes at 37oWith Strahov is whether at the end of the incubation period by heating for 5 minutes at 95oC. Then, the incubation mixture was centrifuged for 3 minutes at 12000 x g and the supernatant was determined by the concentration of unreacted substrate and hydrolysis products resulting from enzymatic reactions. This made the separation of samples of the supernatant liquid by liquid chromatography, high pressure (HPLC) on a hydrophobic silica gel and the products of the enzymatic reaction and unreacted substrate was determined photometrically at a wavelength of 205 nm. When the separation liquid chromatography high pressure was applied to the separation column (4.6 x 125 mm), containing a separating material with reversed phase NucleosinFrom 18.5 microns. The flow of solvent was 1.0 ml/min, the column was heated to 40oC. Fluid medium And served 5 mm H3RHO4pH of 2.5, fluid means In - acetonitrile + 1% 5 mm H3RHO4pH of 2.5.

On the basis of measured concentrations of hydrolysis products and unreacted substrate in the different samples was determined in a known manner the indicator IC50for the tested substances. The test substance obtained in example 2 in this test had the indicator ICthe th inhibitor of neutral endopeptidase.

3. In vivo effects of substances on diuresis/natriuresis in rats with volume load.

Activity in vivo was investigated in the rat with a volume load. In this experiment, the use of isotonic sodium chloride caused a high filling pressure of the heart, which was allocated trially peptide natriyureza happened diuresis/natriyureza.

The test
The experiments were conducted on rats male Wistar weight of from 200 to 400, With neurological analgesia (Fentanyl; Hypnormmanufacturer company Janssen) catheter was inserted in the right femoral vein for background infusion and volumetric load isotonic sodium chloride. After opening the abdominal cavity was entered second catheter in the bladder and the urethra was ligated, which allowed to measure the amount of urine, natriuresis and calibres.

The abdominal cavity was again closed and the animals were injected with a solution of sodium chloride (0.5 ml/100 g body weight) throughout the experiment, which lasted 2 hours. After 30 minutes needed to bring in the equilibrium state, at the stage preceding the input of the test substance, were threefold collection of urine every 10 minutes. These preliminary data outflow of urine.

Then the solutions with the content of the test substances intravenously (injection into the femoral vein) or orally (stomach tube) was administered to groups of 10 rats each. In both applications a control group of animals received only the false solutions not containing the active agent. 5 minutes after intravenous application or 120 minutes after oral administration of substances, rats were loaded with high volume solution of sodium chloride by intravenous injection (2 ml/100 g body weight after 2 min) and collected urine after 60 minutes. Determined the amount formed during this period, urine and measured the content of sodium and potassium. The resulting amount of urine when bulk load testified about the increase in the allocation against the preliminary data.

In the below table. 1 shows the values that increased urine output during large load, and after the introduction of the test substance in % of the number of emitted urine volume load and after administration of placebo. Given the number of excreted sodium and potassium, bulk load and after administration of the test substance, in % of the number of sodium and potassium released during bulk load the following in vivo ECE-inhibitory effect of the substances on rats.

To confirm the inhibitory action exerted by the substances according to the invention, the enzyme conversion of endothelin (ECE), was investigated in a standard test in vivo retarding effect of the substances on the hydrolytic decomposition of big endothelin (BIG ET), resulting enzymatic activity ECE, with the formation of endothelin (ET). Endothelin is a potent sosudosuzhayushcheye autologous substance. Increased levels of endothelin increases blood pressure. When you enter BIG-ET blood pressure increases with education endothelin in the catalytic cleavage of ECE. As the degree of suppression ECE substances determined the effect of slowing down the increase in blood pressure caused by the introduction of big-endothelin.

The test
Experiments were performed on rats male CDfirm Charles River Wiga with body weight from 220 to 280, Under General anesthesia induced by ketamine/xylazine, animals were injected with a single catheter in the left jugular vein for injection of a substance and the other in the left cervical artery for measuring blood pressure. After 30 minutes of rest, the animals were administered the test substance in solution intravenously or II andstc is in the amount of 0.5 nmole/kg The period between application of the test substance and enter the big-endothelin was: when administered intravenously 5 minutes, during intraduodenal the introduction of the tested substances obtained in examples 18 and 22, 15 minutes, the tested substances obtained in examples 8 and 20, 30 minutes. Over the next 30 minutes was measured every 5 minutes systolic and diastolic blood pressure. In animals not treated, the introduction of 0.5 nmole/kg big-endothelin has led to a sharp rise in blood pressure, which was reproducible and lasted about 30 minutes. The maximum rise in blood pressure occurred after approximately 5 minutes.

In table. 2 shows the maximum increase in blood pressure after the introduction of big-endothelin control animals treated with a false solution, and in animals pre-treated with solutions of the test substances with different dosages.

The above test results show that the compounds of formula I have a greater affinity for the enzyme conversion of endothelin and neutral endopeptidase and that depending on the dose by slowing down the enzyme activity of endothelin converting ECE counteract obrazovatelnaya testifies, what substance is also facilitated by inhibition of the enzyme (NEP), destructive trially peptide natriuresis, increased levels in the blood and thereby increase the effects of diuresis/natriyureza caused trialkyl peptide natriyureza, without significant loss of potassium.

Due to the above-described effects of the compounds of formula I last suitable as drugs and for the larger mammals, in particular humans, in the treatment of heart failure and to improve diuresis/natriuresis, especially in patients with heart failure. In this case, the compounds of formula I and their salts, as well as biolabels esters are useful in dosage forms intended for oral administration. The applied dose can be administered individually and naturally vary depending on the condition of the patient, the used substances and dosage forms. In General, however, when assigning to large mammals, in particular humans, suitable dosage form with a content of active substance of from 1 to 200 mg per dose.

As a remedy the compounds of formula I may contain, together with auxiliary substances can be obtained by the known methods using conventional solid or liquid fillers, as, for example, lactose, starch or talcum powder or liquid paraffins, and/or using conventional pharmaceutical auxiliary substances, for example substances for destruction tablets, agents, dissolution or preservatives.

The examples below explain in more detail the invention, without restricting in any case its volume.

The structures of new compounds were confirmed by spectroscopic studies, in particular the analysis of infrared spectra, and, if necessary, by determining the optical values of the rotation.

EXAMPLE 1
Complex benzyl ester of (3S)-3-(1-dibenzylethylenediamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. With stirring, was combined with 100 ml of diversifolia, 12.5 g of paraformaldehyde and 6.2 ml of triethylamine. When slowly heated to 55oWith the temperature raised to 120oC. a Clear solution was cooled to 90oC and stirred at this temperature for 30 minutes. After cooling to room temperature was performed chromatography on 1 kg of silica gel at elevated pressures (solvent: n-hexane/complex ethyl ester acetic acid 1:4). After concentration of fractions and 12 hours of drying OS is used in the reaction without additional purification.

B. 17.8 g dibenzylhydroxylamine was dissolved in 120 ml of dry dichloromethane. After cooling to -50oWith introduced without access of moisture drip and sequentially first of 7.3 g of 2,6-lutidine, then to 10.6 ml of anhydride triftormetilfosfinov acid. The reaction mixture was stirred for one hour at -50oWith, then for a further one hour at 0oC. To separate the mixture was poured into ice water, the organic phase is washed first with dilute ice-cold hydrochloric acid, then with ice water. After drying the organic phase with sodium sulfate and filtering produced evaporation in a vacuum. The resulting crude product was chromatographically on 200 g of silica gel (solvent: n-hexane/complex ethyl ester acetic acid 3:2). After separation and drying of the product fractions were received 17.0 g of oily dibenzylethylenediamine.

C. In nitrogen atmosphere was dissolved without access of moisture to 16.5 ml of Diisopropylamine in 100 ml dry tetrahydrofuran (THF) and cooled to -70oC. To this mixture was added drip 65,5 ml of a 1.6 molar solution of n-utility in n-hexane. Then was stirred for 30 minutes at 0oC, was cooled to -20oAnd ecoaction the mixture was stirred for 30 minutes at -20oC, then for 2 hours at 0oC, then cooled to -60oC. To the mixture drops slowly added to 20.0 g of a solution of the product obtained as described in section B, in 20 ml of tetrahydrofuran. After this addition over 1 hour and stirred at -30oC, then for 1 hour at -20oC. Then the reaction mixture was poured into ice-cold aqueous solution of potassium hydrosulfate and was extracted with methyl tert-butyl ether (MTBE). Separated organic phase was washed her with a saturated solution of sodium chloride, dried with sodium sulfate and after filtration in vacuum were agglomerated. The resulting crude product was purified by chromatography on 300 g of silica gel using pure MTBE, which was mixed with methanol, the content of which is constantly increased from 5 to 10%. Thus obtained product was again chromatographically on 200 g of silica gel with the purpose of further purification, the obtained 6.7 g of pure 1-dibenzyltoluene-1-cyclopentanecarbonyl acid, melting point 89-92oC.

G 24.5 g heated to 65oWith a solution of racemic complex tertiary butyl ether 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid in 54 ml of ethanol was added 12,65 g L-(+)-tartaric acid in 54 ml of hot d is introduced 1,72 ml of benzaldehyde in 1.3 ml of ethanol. The resulting suspension was heated for 14 hours at 80oWith under reflux and cooled to room temperature. The resulting crystalline precipitate was sucked out, was placed in 80 ml of ethanol and again boiled for 8 hours under reflux. Then cooled to room temperature, was pumped out the crystals were dried at will panium pressure and 50oC. Was obtained of 23.6 g of salt of tartaric acid with a melting point 195-196oC; []20D= -152,0(C=0.5 in methanol).

D. To highlight the Foundation of 23.6 g of salt of tartaric acid in a mixture of 250 ml of water and 108 ml of dichloromethane and the mixture was cooled to 0oWith the addition of aqueous ammonia solution brought to a pH of 9.6. Separated organic phase was re-extracted aqueous phase using 30 ml of dichloromethane and agglomerated organic phase was dried with sodium sulfate and were agglomerated under reduced pressure. The remaining precipitate was isolated by crystallization from MTBE and dried under reduced pressure. There was obtained 12.2 g complex tert-butyl ether (3S)-3-amino-2,3, 4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid, melting point 113-115oC; []20oC; []20D= -236,8(C=0.5 in methanol).

J. 5.8 g of the acid obtained above in paragraph B, was placed in 148 ml of dry dichloromethane. In the resulting solution was sequentially added with cooling to the temperature of the ice to 4.8 g of product obtained above, and 3.7 ml of N-methylmorpholine, 1.84 g of 1-hydroxybenzotriazole and 5.8 g of N-(3-dimethylaminopropyl)-N'-Attou temperature. To separate the reaction mixture was diluted with dichloromethane and then washed with water, aqueous solution of potassium hydrosulfate, with water, aqueous sodium carbonate solution and again with water. Drying of the organic phase with sodium sulfate and evaporation in vacuo received of 10.5 g of crude product, which was chromatographically purified on 200 g of silica gel (solvent: n-hexane/complex ethyl ester acetic acid, 3: 7). After evaporation of the product fractions and drying in vacuum allocated 6.5 g of pure compound indicated in the title of example, in the form of a solid foam, infrared spectrum: 3400, 3310, 2940, 1740, 1650 cm-1(film); []20D= -104,6(C=0,754 in methanol).

EXAMPLE 2
(3S)-3-(1-Phosphonomethylglycine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. 1.9 grams of complex benzyl ester of (3S)-3-(1-dibenzylethylenediamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1G) was dissolved in 100 ml of ethanol. Was added 1.2 g of a 5% palladium catalyst on charcoal and was first made for 3 hours under hydrogen pressure of 5.5 bar. For the separation of Catalu the form of a foamy product, infrared spectrum: 3400, 1720, 1630 cm-1(KBr); []20D= -140,8(C=0.5 in methanol).

B. 701 mg) obtained above free acid and 238 mg of sodium carbonate was dissolved in 60 ml of water, the solution was evaporated in vacuum. The precipitate was mixed with a small amount of MTBE and again evaporated in vacuo. Resulting solid foam was isolated from isopropanol crystallization, the crystals were separated from the solvent and dried for two days at 60oWith in high vacuum. Received 700 mg of sodium salt mentioned in the title of the example compound, melting point >270oC; []20D= -159,7(C=0,149 in methanol).

EXAMPLE 3
Complex benzyl ester of (3S)-3-(1-benzylidenemethylamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. Under ice cooling, 8.0 g of NaOH in 30 ml of water and 30 ml of ethanol droplet was added to 27,6 g diethylphosphate and was stirred for 2 hours at room temperature. Then was evaporated in vacuum and was extracted with water balance four times with MTBE. After evaporation of the aqueous phase in the Waco without additional purification.

B. In 33,9 g of the solution of hydrosulphate of Tetra butylamine in 20 ml of water drip was added under ice cooling, 4.0 g NaOH in 22 ml of water, and the temperature was maintained below 25oC. Then was added drip at room temperature of 12.5 g of product obtained above, dissolved in 15 ml of water. After 15-minute stirring was produced by the suction phase precipitates of sodium sulfate and the filtrate was extracted 4 times with 50 ml dichloromethane. The combined organic phase was dried with sodium sulfate and evaporated in vacuum. The residue was dried for one hour at 40oWith the vacuum, was dissolved in 120 ml of anhydrous acetonitrile and was mixed into 7,07 ml benzylbromide and 0.4 g of sodium iodide. Was stirred for 12 hours at 50oWith separated the solvent in vacuo and placed the remainder in n-hexane. Was aspirated solid residue, optionally washed with a mixture of n-hexane and MTBE, and dried. The resulting solution was evaporated in vacuo, the residue was chromatographically on 200 g of silica gel (solvent: n-hexane/complex ethyl ester acetic acid 2:3). Received 6.7 g of bansilalpet in the form of oil, infrared spectrum: 2420, 1255, 970 cm-1(film).

Century 18.0 g of the above product was introduced in the interaction with 2.5 g paraformal: complex ethyl ester of acetic acid) was obtained 16.5 g benzylidenemalonate in the form of oil, infrared spectrum: 3300, 1230, 1030 cm-1(film).

G 12.0 g product obtained above was brought into interaction with 6.2 g of 2,6-lutidine and 9.0 ml of anhydride of triftoratsetata the method described in example 1B. Chromatography on 200 g of silica gel (solvent: n-hexane/complex ethyl ester acetic acid 2:3) received 16.3 g of oily benzyltrifluoromethanesulfonamide, infrared spectrum: 1410, 1245, 1210, 1010 cm-1(film).

D. From 16,08 ml Diisopropylamine, 63,8 ml of a 1.6 molar solution of n-utility in n-hexane and 5.3 ml cyclopentanecarbonyl acid was obtained by the method described in example 1B, dianion cyclopentanecarbonyl acid and brought into interaction described there the same way with 16.0 g of the product obtained as described in paragraph (G Chromatography of the crude product on 300 g of silica gel (solvent: first n-hexane/complex ethyl ester acetic acid 1:1, which is then gradually replaced the pure complex ethyl ester of acetic acid) was received and 7.1 g of pure oily 1-(benzylaminocarbonyl)-1-cyclopentanecarboxylic acid, infrared spectrum: 2950, 1720, 1210, 1175, 1010 cm-1(film).

That is, 3.1 g acid obtained above was introduced into interaction with 3.2 g of benzyl complex e is orfelina, 1.35 g of hydroxybenzotriazole and 3.8 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide-hydrochloride by the method described in example 1G. Chromatography on 200 g of silica gel (solvent: complex ethyl ester of acetic acid) was obtained 2.3 g of the title compound as a viscous oil, infrared spectrum: 3410, 2940, 1735, 1660, 1230, 1020 cm-1(KBr); []20D= -121,6(C= 0,495 in methanol).

EXAMPLE 4
Complex ethyl ester of (3S)-3-(1-benzylidenemethylamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. 5.0 g complex tert-butyl ether (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid (receipt, see example 1D) and 3.75 g of p-toluenesulfonic acid was boiled in 80 ml of toluene for 2.5 hours on a water separator. Then were added to separate portions of ethanol in the total amount of 200 ml, the resulting reaction mixture was heated for 3.5 hours under reflux. After that was agglomerated mixture in vacuo, the residue was placed in dichloromethane. Mixed by shaking with ice-cold sodium carbonate solution and neutrally washed the organic phase with water. The organic phase was dried sulphate soda,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid, melting point: the 106.5-108oC; infrared spectrum: 3350, 3300, 2930, 1735, 1660 cm-1(film); []20D= -288,4(C=0.5 in methanol).

B. 3.1 g of 1-(benzylaminocarbonyl)-1-cyclopentanecarbonyl acid (receipt, see example 3D) was introduced in the interaction with 2.6 g of product obtained above, and 3.3 ml of N-methylmorpholine, 1.35 g of hydroxybenzotriazole and 3.8 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide-hydrochloride by the method described in paragraph (1G. Chromatography on 200 g of silica gel (solvent: first n-hexane/complex ethyl ester acetic acid 1:1, which is then continuously changed to obtain a composition of 3:7) was obtained 3.7 g mentioned in the title of the example compounds in the form of oil, infrared spectrum: 3410, 2950, 1735, 1660 cm-1(film); []20D= -113,6(C=0,639 in methanol).

EXAMPLE 5
Complex ethyl ester of (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

3.2 g of complex ethyl ester (3S)-3-(1-benzylidenemethylamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (from the hydrogen 2.2 bar way described in example 2. After the division received 2.4 g mentioned in the title of the example compounds in the form of a foamed resin, an infrared spectrum: 3400, 2950, 1740, 1650 cm-1(KBr); []20D= -162,0(C=0,324 in methanol).

EXAMPLE 6
Complex ethyl ester of (3S)-3-[1-(pivaloyloxymethyl)cyclopentane-1-carbylamine] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

0.6 g of complex ethyl ester (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 5) was dissolved without access moisture in 20 ml of dimethylformamide (DMF) was then added to 1.86 ml of triethylamine, to 0.88 ml pivaloyloxymethyl and 0.1 g of dimethylaminopyridine. The reaction mixture was stirred overnight, the solvent evaporated under reduced pressure and put the residue in dichloromethane. The organic phase is washed with water and then dried with sodium sulfate. After thickening, the vacuum was obtained the crude product, which was chromatographically to clean it on 50 g of silica gel (solvent: first n-hexane/complex ethyl ester acetic acid, 3:7, then the contents of ether gradually brought up to 100%). ub>2
CL2); []20D= -124,1(C=0,228 in methanol).

EXAMPLE 7
Complex ethyl ester (3S)-3-[1-(5-intenlational)cyclopentane-1-carbylamine] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

480 mg complex ethyl ester (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 5) was dissolved in 10 ml of dry dichloromethane and was entangled, and 0.28 ml of triethylamine. The resulting solution was cooled to -50oC, then added to it and 0.09 ml of oxalicacid. Then to the reaction mixture was mixed into at -50oWith 200 mg of 5-indanol, was heated to 0oC and was stirred at room temperature for 5 hours. The organic phase is washed with water, separated, dried with sodium sulfate and evaporated under reduced pressure. After chromatography on 80 g of silica gel (solvent: n-hexane/complex ethyl ester acetic acid 1:1, and the ratio of solvent continuously changed to the ratio 1:4) after drying in high vacuum was obtained 220 mg specified in the title of the example compounds in the form of a viscous resin, an infrared spectrum: 1740, 1655 cm(C=0,205 in methanol).

EXAMPLE 8
Complex tert-butyl ether (3S)-3-(1-benzylidenemethylamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

5.0 g of 1-(benzylaminocarbonyl)-1-cyclopentanecarbonyl acid (receipt, see example 3D) enter into interaction with 5,15 g complex tert-butyl ether (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1D), with 4.1 ml of N-methylmorpholine, 2.0 g of hydroxybenzotriazole and 6.3 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide-hydrochloride by the method described in example 1G. The resulting crude product was chromatographically on 200 g of silica gel (solvent: first n-hexane/complex ethyl ester acetic acid 1:1, then pure ester). Received 2.6 g mentioned in the title of the example compounds in the form of a foamed resin, an infrared spectrum: 3410, 3350, 1735, 1655 cm-1; []20D= -118,1(C= 0,609 in methanol).

EXAMPLE 9
Complex benzyl ester of (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

A. 3.5 g of 1-(benzylaminocarbonyl)-1-cyclopentanecarbonyl acid (policosanol coal. Then was first made for 4 hours under hydrogen pressure of 2.1 bar. Twice was filtered, the catalyst was evaporated in vacuo and dried in high vacuum. Received 2,60 g of oily 1-ethylphosphonate-1-cyclopentanecarboxylic acid, which was used in the reaction without additional purification.

B. 2.6 g product obtained above was dissolved without access of moisture in 100 ml of dry dichloromethane, was mixed into 3.5 g of carbonyldiimidazole and of 3.56 g complex benzyl ester of (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1E) and was stirred over night. Then was poured into a saturated aqueous solution of potassium hydrosulfate, washed neutral with water the organic phase was dried with sodium sulfate. The resulting crude product was chromatographically on 150 g of silica gel (solvent: first complex ethyl ester acetic acid, which then gradually mixed into dichloromethane, while the ratio of solvent was 1:1).

After drying of the product fractions under vacuum was obtained 1.4 g mentioned in the title of the example compounds in the form of foam, infrared spectrum: 3410, 1740, 1645 cm-1(KBr); []20D= -130,7amino)-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

A. 69,05 g diethylphosphate entered into interaction with 14.5 g of paraformaldehyde and from 6.69 ml of triethylamine by the method similar to that described in example 1A. Received 66,02 g diethylhydroxylamine, which after drying in a high vacuum without additional purification was used in subsequent reactions.

B. 21,02 g obtained above phosphonate, 15.0 g of 2,6-lutidine and 21.8 ml of anhydride of triftoratsetata entered into interaction with a method described in example 1B. Received of 32.5 g of oily diethylphosphonoacetate.

B. 30.0 g obtained above triftormetilfullerenov entered into interaction with 133 ml of a 1.6 molar solution of n-utility in n-hexane and from 10.8 ml cyclopentanecarbonyl acid by the method described in example 1B. Got to 11.1 g diethylphosphonate-1-cyclopentanecarboxylic acid, infrared spectrum: 2970, 1730, 1240, 1030 cm-1(film).

He 5,74 g obtained above carboxylic acid derivative was introduced into interaction with 7,05 g complex benzyl ester of (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1E) in the manner described in example 1G. The resulting crude product was purified by chromatography on silica gel (solvent: complex ethyl ester p>-1(film); []20D= -130,3(C=0,538 in methanol).

EXAMPLE 11
(3S)-3-(1-Diethylphosphonoacetate-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

5.3g complex benzyl ester of (3S)-3-(1-diethylphosphonate-1-cyclopentane-1-carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid (receipt, see example 10) was dissolved in 250 g of ethanol, mixed with 1.5 g of a 5% palladium catalyst on charcoal and was first made by the method described in example 2. Received 4.3 g mentioned in the title of the example compounds, infrared spectrum: 3390, 1730, 1650 cm-1(KBr); []20D= -156,6(C=0,514 in methanol).

EXAMPLE 12
Complex ethyl ester of (3S)-3-(1-diethylphosphonoacetate-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

of 2.34 g of (3S)-3-(1-diethylphosphonoacetate-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 11) was dissolved without access moisture in dichloromethane, mixed with 1.6 ml of N-methylmorpholine, to 0.63 g of 1-hydroxybenzotriazole, 2.0 g of N-(3-dimethyl is the temperature value. Then the reaction mixture is then washed with water, a solution of potassium hydrosulfate, water, sodium hydrogen carbonate solution and again with water. After separating the organic phase, dried with sodium sulfate and evaporated in vacuum. The product was chromatographically on 200 g of silica gel (solvent: first, ethyl ester acetic acid, and later it was added 5% methanol), the fraction of the product was enriched and dried in vacuum. Received 1.6 g mentioned in the title of the example compounds, infrared spectrum: 3410, 1740, 1650, 1200, 1030 cm-1(film); []20D= -126,1(C=0,584 in methanol).

EXAMPLE 13
Complex ethyl ester of (3S)-3-(1-phosphonomethylglycine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

1.3 g of complex ethyl ester (3S)-3-(1-diethylphosphonoacetate-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 12) was dissolved under nitrogen atmosphere in 13 ml of dichloromethane. While cooling with ice was mixed into 0.5 ml of bromotrimethylsilane and 0.4 ml of triethylamine and stirred overnight. The excess solvent was removed in vacuum, the residue is stirred in techville a small amount of dichloromethane, and mixed from 0.53 g of (S)-(-)--methylbenzylamine. Precipitated precipitated solid was separated from the ethanol by recrystallization, and is indicated in the name of the example compound was obtained as a saltmethylbenzylamine with a melting point 210-213oC. the Infrared spectrum: 2940, 1750, 1650, 1200, 1045 cm-1(CVG); []20D= -141,0(C=0.2 in methanol).

EXAMPLE 14
Complex benzyl ester of (3S)-3-1-phosphonomethylglycine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

3.8 g of complex benzyl ester of (3S)-3-(1-diethylphosphonate-1-cyclopentane-1-carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid (receipt, see example 10) was dissolved in 10 ml of dichloromethane while cooling with ice mixed with 10.3 ml triperoxonane acid and was stirred for 18 hours at room temperature. The solvent is separated in a vacuum, the remaining residue was repeatedly treated with toluene and again evaporated. The resulting crude product was dissolved in dichloromethane, washed three times with water, then the separated organic phase was dried with sodium sulfate and the solvent evaporated in accracy range: 3400, 2950, 1745, 1640 cm-1(CVG); []20D= -146,5(C=0.2 in methanol).

EXAMPLE 15
Complex benzyl ester of (3S)-3-(1-diisopropylphosphoramidite-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. 50.0 g of Diisopropylamine, 8.5 g of paraformaldehyde and 4.0 ml of triethylamine were introduced into the interaction by the method described in example 1A. After chromatography of the crude product on silica gel (solvent: n-hexane/complex ethyl ester acetic acid 1:4) received 37,5 g diisopropylethylamine in the form of oil, which was further used without purification.

B. 19,6 g obtained above compounds were introduced into the interaction from 17.4 ml of anhydride of triftoratsetata and 11,96 g of 2,6-lutidine in the manner described in example 1B. After chromatography of the crude product on silica gel (solvent: n-hexane/complex ethyl ester acetic acid, 3:7) received a 27.4 g diisopropylphosphoramidite in the form of oil, infrared spectrum: 2980, 1410, 1205, 1000 cm-1(film).

Century 27,4 g obtained above compounds of 10.05 ml cyclopentanecarbonyl acid and 120 ml of a 1.6 molar solution of n-utility in n-hexane was introduced into VSL: first n-hexane/complex ethyl ester acetic acid, 3: 7, in which gradually entangled in a growing number of ester to 100%) was obtained 10.6 g diisopropylaminomethyl-1-cyclopentanecarbonyl acid with a melting point 53-57oC.

He 2,05 g obtained above compounds were introduced into interaction with 2.24 g of complex benzyl ester of (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1E) in the manner described in example 1G. Received 3.5 g mentioned in the title of the example compounds in the form of oil, infrared spectrum: 3410, 1735, 1650, 1240, 1180 cm-1(film); []20D= -127,5(C=0,287 in methanol).

EXAMPLE 16
Complex ethyl ester of (3S)-3-(1-benzylidenemalononitrile-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. 92.0 ml Diisopropylamine and 22.2 g of NaOH was injected into the interaction by the method described in example 3A. Received 88.0 g of isopropylmyristate sodium, which is used in the reaction without additional purification.

B. 88.0 g obtained above compounds and 34 ml of benzylbromide was introduced in the interaction method similar to that described in example 3B. Received 46,3 g benzylidenemalonate in the form of oil, to the interaction with 6.1 g of paraformaldehyde are 2.87 ml of triethylamine way described in example 1A. Received 24,0 g benzylidenemalonate in the form of oil, IR range: 3300, 1230, 995 cm-1(film).

He 24,0 g obtained above compounds were introduced into interaction with to 18.01 ml of anhydride of triftoratsetata and 13,57 ml of 2,6-lutidine in the manner described in example 1B. Received 32,5 g benzylidenemalononitrile in the form of oil, infrared spectrum: 2980, 1410, 1245, 1000 cm-1(film).

D. 32,5 g obtained above compounds, 9,65 ml cyclopentanecarbonyl acid and 13.4 ml of a 1.6 molar solution of n-utility in n-hexane was introduced into the interaction by the method described in example 1B. After chromatography of the crude product on silica gel (solvent: first n-hexane/complex ethyl ester acetic acid 1:1, then the pure ester, then complex ethyl ester of acetic acid containing 5% vol. isopropanol) was obtained 7.0 g of 1-benzylidenemalononitrile-1-cyclopentanecarboxylic acid, which was used in the reaction without additional purification.

E. 1,25 g obtained above compounds and 1.06 g of complex ethyl ester (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 4A) was introduced in the interaction method, o, 985 cm-1(film); []20D= -123,0(C=0.1 in isopropanol).

EXAMPLE 17
Complex tert-butyl ether (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

2.2 g of complex tert-butyl ether (3S)-3-(1-benzylidenemethylamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 8) was first made using 1.0 g of a 5% palladium catalyst on charcoal as described in example 2, when the hydrogen pressure of 2.5 bar. Received 1.7 g mentioned in the title of the example compounds, infrared spectrum: 3470, 1735, 1650 cm-1(film); []20D= -158,2(C=0,515 in methanol).

Example 18
Complex tert-butyl ether (3S)-3-[1-(pivaloyloxymethyl-ethylphosphonate)cyclopentane-1-carbylamine] -2,3,4,5 - tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

0.6 g of complex tert-butyl ether (3S)-3-(1-acylphosphatidylethanolamine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 17) was introduced in vsamom in example 6. After chromatography on silica gel (solvent: complex ethyl ester of acetic acid) received 392 mg specified in the title of the example compounds in the form of a viscous resin, an infrared spectrum: 1740, 1650 cm-1(CH2CL2); []20D= -122,9(C=0,257 in methanol).

For example 20.

The salt form is a complex tert-butyl ether (3S)-3-(1-phosphonomethylglycine-1 carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A. 961 mg of the above, the free phosphonic acid was mixed with 212 mg of sodium carbonate and 20 ml of water. The resulting mixture was filtered, the resulting filtrate evaporated in vacuum. The resulting residue was separated from the ethanol by crystallization, the crystals were dried overnight in vacuum at 60oC. Received 750 mg of sodium salt of the title compound, melting point >270oC; []20D= -141,5(C=0.25, methanol).

B. 961 mg above the free phosphonic acid was dissolved in 20 ml of MTBE and mixed 0.42 ml of tert-butylamine. The resulting solution was evaporated in vacuo, the resulting residue was placed in a mixture of MTV>the. Received 950 mg ammonium salts mentioned in the title of the example compounds, the melting point 215-220oC; []20D= -149,8(C=0.26 in methanol).

The methods described in the examples above, can be obtained the compounds of formula I listed in table. 3.

Example 1. Drug.

Capsules containing complex tert-butyl ether (3S)-3-[1-(pivaloyloxymethyl)cyclopentane-1-carbylamine] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid.

Prepare capsules, each of which has the following composition,mg:
Complex tert-butyl ether (3S)-3-[1-(pivaloyloxymethyl)cyclopentane-1-carbylamine] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid - 20
Corn starch - 60
Lactose - 301
Complex ethyl ester acetic acid, a Sufficient amount of
Of the active substance, corn starch and lactose using complex ethyl ester acetic acid was prepared in a homogeneous pasty mixture. The paste was crushed, the resulting granules were placed on the appropriate tray and dried at 45oWith removal of the solvent. Dried granp:
Talc - 5
Magnesium stearate - 5
Corn starch - 9
Then capsules with a capacity of 400 mg (capsule size=0) completed.


Claims

1. Derivative benzazepine-N-acetic acid, substituted phosphonic acid of the General formula I

where R1means hydrogen or a group forming biolabeling ester phosphonic acid;
R2means hydrogen or a group forming biolabeling ester phosphonic acid;
R3means hydrogen or a group forming biolabeling ester of carboxylic acid,
and physiologically acceptable salts of the acids of formula I.

2. Connection on p. 1, in which R3means hydrogen or lower alkyl.

3. Drug, possessing inhibiting neutral endopeptidase activity, containing a pharmacologically effective amount of the compounds under item 1, as well as conventional pharmaceutical excipients and/or fillers.

4. The method of obtaining derivatives of benzazepine-N-acetic acid, substituted phosphonic acid of General formula

where R1means hydrogen or a group forming biology ester phosphonic acid,
R3means hydrogen or a group forming biolabeling ester of carboxylic acid,
physiologically acceptable salts of acids of the formula I, characterized in that to obtain the compounds of General formula IV

where R101and R201, independently of one another, mean hydrogen or a protective group of the phosphonic acid;
R302means a protective group of carboxylic acid,
compounds of General formula II

where R101and R201have the above values,
enter into an interaction with compounds of General formula III

where R302has the above value,
and if R101and/or R201mean hydrogen-free function (available options) phosphonic acid, if necessary, by esterification with a compound of General formula Va and/or Vb,
R110-Y (Va), R210-Y (Vb),
where R110and R210correspondingly represent a group forming biolabeling ester phosphonic acid;
Y represents a hydroxyl radical or tsepliaeva volatile group,
transferred to biolabels broadcasting group, phosphonic acid, and if inside the what they biolabeling ester, they otscheplaut simultaneously or separately one after another in any sequence and, if desired, transfer the appropriate released acid functions in biolabeling ester group, Emeryville when available functions phosphonic acid with the compound of the formula Va or Vb, and/or available options carboxylic acid with a compound of General formula Vc
R310-Y (Vc)
where R310means a group forming biolabeling ester carboxylic acid;
Y has the above meaning,
and, if necessary, the acid of formula I is transferred to their physiologically acceptable salts or salts of acids of formula I into the free compound.

 

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< / BR>
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< / BR>
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