MXPA06014448A - Pharmaceutical compositions comprising nep-inhibitors, inhibitors of the endogenous endothelin producing system and at1-receptor antagonists. - Google Patents

Abstract

A novel combination therapy is described for cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and/or congestive heart failure, involving administering a synergistic combination of at least one inhibitor of neutral endopeptidase, at least one inhibitor of the endogenous endothelin producing system and at least one AT1 receptor antagonist.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING NEP INHIBITORS, INHIBITORS OF ENDOGENOUS ENDOTHELINE PRODUCER SYSTEM AND ATX RECEPTOR ANTAGONISTS The present invention relates to a new combination therapy for cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and / or congestive heart failure, by a synergistic combination of, at least one neutral endopeptidase inhibitor (NEP), at least one inhibitor of the endogenous endothelin producing system and at least one ATi receptor antagonist. Therefore, the invention also relates to new pharmaceutical compositions comprising NEP inhibitors, inhibitors of the endogenous endothelin producing system and ATi receptor antagonists and to the use of said pharmaceutical composition in the prophylaxis or treatment of cardiovascular diseases in mammals and humans. The nature of cardiovascular diseases, in particular vascular hypertensive, is multifactorial. Combination therapy has been shown to address the multiple pathophysiological factors that play a role in the elevation of blood pressure, which includes blood volume, vasoconstriction, and the impact of the sympathetic nervous system and the activity of the Renin-Angiotensin-Aldosterone system ( RAAS) [see, for example, MR eir, American Journal of Hypertension 1_1 (1998) 163S-169S], potentially leading to a greater reduction in blood pressure and lower risks of deterioration of the target organ. The use of a fixed combination agent in low doses could also offer lower doses of each component than those that may be necessary with monotherapy, reducing, therefore, the risks of adverse cases that depend on the dose and the problems of compliance associated. It is known from EP 0 254 032 A2 that NEP inhibitors can lower blood pressure under conditions in which inhibitors of enzymes that are converted to angiotensin (ACE) as monotherapy are relatively ineffective. In addition, this document describes that NEP inhibitors can be combined with other drugs used in the treatment of hypertension, for example, ACE inhibitors, to increase the effects of these drugs. Accordingly, pharmaceutical compositions comprising a NEP inhibitor and an ACE inhibitor are described. WO 03/059345 Al provides pharmaceutical compositions comprising a specific antagonist of the ATi receptor, valsartan, and NEP inhibitors for the treatment or prevention of, among others, cardiovascular diseases.

Although the beneficial role of compounds that inhibit NEP in the treatment or prevention of cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and / or congestive heart failure, is widely recognized at present, its action profile is still suffering from certain deficiencies inherent In congestive heart failure, as a result of the lower volume of cardiac output and the increase in peripheral resistance, phenomena of counter-pressure of blood in the pulmonary circulation and in the heart itself take place. As a result, a greater tension of the heart muscle wall takes place in the area of the atria and chambers. In such a situation, the heart functions as an endocrine and secret organ, among others, the atrial natriuretic peptide (ANP) in the bloodstream. Due to its marked vasodilator and natriuretic / diuretic activity, the ANP causes a reduction in peripheral resistance and a decrease in the volume of circulating blood. The consequence is a marked decrease in pre- and afterload. This constitutes an endogenous cardioprotective mechanism. This endogenous positive mechanism is limited because ANP has only a very short half-life in the plasma. The reason for this is that the hormone is broken down very quickly by NEP. Therefore, the pharmacological inhibition of NEP increases the levels of ANP and, therefore, stimulates this cardioprotective mechanism. In congestive heart failure, due to a lower volume of cardiac expansion, related to the disease, there is a reflex increase in peripheral vascular resistance. As a result, the heart muscle must start pumping against a greater post-load. In a vicious circle, this results in a greater effort on the heart and further aggravates the situation. The increase in peripheral resistance is arbitrated, inter alia, by the vasoactive peptide endothelin. Endothelin (ET) is the strongest endogenous vasoconstrictor currently known and is formed from the precursor large endothelin (bigET) with the participation of the enzyme that becomes endothelin (ECE). NEP is involved not only in the decomposition of ANP, but also in the decomposition of endothelin. For these reasons, a combination of compounds that have NEP inhibitory activity with compounds capable of inhibiting the system that produces endogenous endothelin or compounds with dual inhibitory activities on NEP and the system that produces endogenous endothelin, seems to provide added value in the therapy of diseases. cardiovascular diseases such as essential hypertension, pulmonary hypertension and / or congestive heart failure. As a result of the inhibition of the system that produces endogenous endothelin, the formation of endothelin would be avoided and, therefore, the increase in peripheral resistance would be neutralized, which leads, consequently, to a relief of the stress on the cardiac muscle. As a result of the inhibition of the NEP enzyme that degrades ANP, higher ANP levels and a longer duration of ANP action can be achieved. This will lead to a reinforcement of the mechanism of endogenous cardioprotective action by means of ANP. However, because NEP may also be involved in the degradation of ET, a pure inhibition of NEP, in addition to the desired increase in ANP levels, will also lead to an unfavorable increase in ET levels. For this reason, a mixed profile with the inhibition of double action of NEP and the system that produces endogenous endothelin has to be considered as particularly favorable, since it avoids both the decomposition of the ANP that acts natriuretically / diuretically (by blockade of NEP) as, simultaneously, it inhibits the formation of ET. As a result, the concomitant adverse effect of pure NEP inhibitors (increased endothelin levels) is no longer produced. Compounds with a dual action combined inhibitory effect on NEP and the system producing endogenous endothelin, ie, benzazepin-, benzoxazepin- and benzothiazepine-N-acetic acid derivatives, are known from EP 0733642 Al. Additional favorable pharmacological properties of compounds falling within the structural scope of EP 0733642 Al are known from EP 0830863 Al, WO 00/48601 Al and WO 01/03699 Al. Derivatives of benzazepinone-N-acidic acid substituted with phosphonic acid, with a Combined inhibitory effect on NEP and the endogenous endothelin-producing system are described in EP 0916679 A1. Derivatives of 1- (carboxyalkyl) -cyclopentylcarbonylamino-benzazepine-N-acetic acid with amidomethyl substitution which are useful, for example, for prophylaxis and / or treatment of cardiovascular conditions or diseases are described in WO 2005/030795 Al. WO 02/094176 A2 is known to Certain compounds, including those described in EP 0733642 A1 and in EP 0916679 Al, can inhibit the system that produces endogenous endothelin via the inhibition of IGS5 metalloprotease. The IGS5 metalloprotease is also known as soluble human endopeptidase (hSEP) and is described in WO 02/094176 A2. In addition, WO 02/094176 A2 describes the use of compounds with combined NEP / hSEP inhibitory activity for the prophylaxis or treatment of, among others, cardiovascular diseases. It is the object of the present invention to provide a new combination therapy for cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and / or congestive heart failure, with better efficacy and a favorable safety profile. Surprisingly it has now been discovered that the combination of at least one NEP inhibitor, at least one endogenous endothelin-producing system inhibitor and additionally, at least one ATi receptor antagonist, provides even better efficacy in cardiovascular diseases such as essential hypertension , pulmonary hypertension and / or congestive heart failure, and a favorable safety profile. The invention therefore relates, in a first aspect, to pharmaceutical compositions comprising pharmacologically effective amounts, each of: a) at least one inhibitor of NEP as the first active agent, b) at least one inhibitor of the system that produces endogenous endothelin as the second active agent, and c) at least one ATi receptor antagonist as the third active agent. The pharmaceutical compositions according to the invention may further comprise, and preferably, pharmaceutically acceptable excipients and / or excipients. The pharmaceutical compositions according to the invention may further comprise acetylsalicylic acid. Inhibitors of the system that produces endogenous endothelin can be chosen in the group consisting of ECE inhibitors, hSEP inhibitors and double-acting compounds capable of inhibiting ECE and hSEP. Double action compounds capable of inhibiting ECE and hSEP are preferred. In the pharmaceutical compositions according to the invention, the sub-combination of at least one NEP (a) inhibitor and at least one endogenous endothelin (b) producing system inhibitor can be preferably carried out by a double-acting compound capable of inhibiting NEP and the system that produces endogenous endothelin. Double-acting compounds, capable of inhibiting NEP and hSEP are preferred. Particularly preferred are the double-acting compounds of the general formula I, wherein: R1 is hydrogen or a group that forms a biolabile carboxylic acid ester, A represents a group chosen in subgroups a, R3 wherein: R 2 is hydrogen or a group forming a biolabile ester of carboxylic acid, and R 3 is a phenyl-C 1 alkyl group - which may optionally be substituted on the phenyl ring with C 1 - alkyl, C 2 alkoxy -4 or halogen; or a naphthyl-C de -4 alkyl group; or b, O R5 ° -p \ b R40 in which: R4 is hydrogen or a group that forms a biolabile phosphonic acid ester and R5 is hydrogen or a group that forms a biolabile phosphonic acid ester; or c, wherein: R6 is hydrogen or a group forming a biolabile carboxylic acid ester, R7 is hydrogen, C? - alkyl or C? -4 hydroxyalkyl, whose hydroxyl group is optionally esterified with C2-4 alkanoyl or a amino acid residue, and R8 is C? - alkyl; Cl- (C) alkyl alkoxy; hydroxyalkyl of C? -, which is optionally substituted with a second hydroxyl group and whose hydroxyl groups are each esterified, optionally, with C2.4 alkanoyl or an amino acid residue; (C0-4 alkyl) 2-amino-Ci-e alkyl; C3-7 cycloalkyl; C3-C3-C4-4alkyl; phenyl-C 1 -4 alkyl, which phenyl group is optionally substituted 1-2 times with C 4 -4 alkyl, C 1 alkoxy and / or halogen; Naphthyl-C? -4 alkyl; C3_6 oxyalkyl; phenylcarbonylmethyl, whose phenyl group is optionally substituted 1-2 times with C? -4 alquilo alkyl, C? -4 alco alkoxy and / or halogen, or 2-oxoazepanyl, or R7 and R8 together are C4-7 alkylene, whose groups methylene are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and / or sulfur and which are optionally substituted once with hydroxyl, which is optionally esterified with C 2-4 alkanoyl or an amino acid residue; C? -4 alkyl; Ci-4 hydroxyalkyl, the hydroxyl group of which is optionally esterified with C2-4 alkanoyl or an amino acid residue; phenyl or benzyl, and / or physiologically compatible acid salts of acids of the Formula I and / or physiologically compatible acid addition salts of compounds of the Formula le. When the substituents on the compounds of the Formula I are or contain C? -4 alkyl groups, they may be straight or branched chain. When the groups forming biolyable ester in the compounds of Formula I are or contain lower alkyl groups, these may be straight or branched chain and usually contain 1 to 4 carbon atoms. When the substituents contain halogen, fluorine, chlorine or bromine, preferably fluorine or chlorine are particularly suitable. When the substituents contain C2_4 alkanoyl, it may be straight or branched chain. Acetyl is preferred as C2_4 alkanoyl. When the substituents are biolabile ester-forming groups, they generally represent prodrugs of the drug active substance. Prodrugs are therapeutic agents that are inactive per se, but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the main drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and target limitations (see, eg, Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: FD King, p.215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14. (3), 277-280, 2004; P. Ettmayer et al., "Lessons learned from marketed and investigated. tiona l prodrugs ", J. Med. Chem., 47, 2393-2404, 2004). Suitable physiologically compatible salts of free acids or partial esters of Formula I include their alkali metal, alkaline earth metal or ammonium salts, for example sodium or calcium salts or salts with physiologically compatible and pharmacologically neutral organic amines, such as, for example , diethylamine or tert-butylamine. Preferred are the compounds of the general formula wherein R1, R2 and R3 have the above meanings, and physiologically compatible salts of acids of Formula la. Preferred salts of compounds of the Formula are described, for example, in WO 03/059939 Al which is incorporated herein by reference. The compounds of the Formula contain two chiral carbon atoms, mainly the carbon atom which is in the 3-position of the ring skeleton (position 3) and carries the amide side chain, and the carbon atom of the amide side chain which it carries the radical R3 (position 2 '). The compounds can therefore exist in various optically active stereoisomeric forms or as a racemate. In accordance with the present invention, both the racemic mixtures and the isomerically pure compounds of Formula Ia can be used.

The compounds of Formula I are dicarboxylic acid derivatives, optionally esterified. Depending on the form of administration, biolabile monoesters are preferred, particularly compounds wherein R2 is a group forming a biolyable ester and R1 is hydrogen, or dicarboxylic acids, the latter being particularly suitable for i.v. Groups which can be divided under physiological conditions in vivo, which release bi-usable derivatives of the compounds of Formula la, are suitable as groups forming biolábile esters of carboxylic acids R1 and R2. Suitable examples of this are C alquilo - alkyl groups, in particular methyl, ethyl, n-propyl, and isopropyl; C 1-4 alkyloxy groups C 1-4 alkyloxy C 1-4 alkyl in particular methoxyethoxymethyl; C3-7 cycloalkyl groups, in particular cyclohexyl; cycloalkyl groups of C 3-7-C 4 alkyl, in particular cyclopropylmethyl; N, N-di- (C0-4 alkyl) amino-C-6 alkyl groups; phenyl or phenyl-C de4 alkyl groups optionally substituted on the phenyl ring once or twice with halogen, C? -4 alquiloalkyl or C alco _ alkoxy or with a C? -4 al alkylene chain attached to two adjacent carbon atoms; dioxolanylmethyl groups optionally substituted on the dioxolane ring with C? _ alkyl; C2-6 alkanoyloxyC ~ -4 -4alkyl groups optionally substituted on the oxy-C de _ alkyl group with C? -4 alquilo alquiloalkyl; double esters such as esters of C 1 -4 - [[(C 1 -4) alkylcarbonyl] oxy] alkyl, for example, (RS) -1 - [[(isopropyl) carbonyl] oxy] ethyl or ( RS) -l - [[(ethyl) carbonyl] oxy] -2-methylpropyl (for its preparation, see for example, FW Sum et al., Bioorg.Med. Chem. Lett. 9 (1999) 1921-1926 or Y Yoshimura et al., The Journal of Antibiotics 39/9 (1986) 1329-1342); carbonate esters such as esters of 1- [[(C4_7 cycloalkyloxy) carbonyl] oxy] C4-4 alkyl, preferably (RS) -l - [[(cyclohexyloxy) carbonyl] oxy] ethyl (cilexethyl; its preparation, see, for example, K. Kubo et al., J. Med. Chem. 36 (1993) 2343-2349, cited as "Kubo et al." hereafter) or esters of 2-oxo-l, 3 -dioxolan-4-yl-C-4 alkyl, which optionally contain a double bond in the dioxolane ring, preferably 5-methyl-2-oxo-l, 3-dioxolen-4-yl-methyl (medoxomil, for its preparation see, for example, Kubo et al.) or 2-oxo-l, 3-dioxolan-4-yl-methyl ((methyl) ethylene carbonate). When the group forming a biolabile ester represents an optionally substituted phenyl-C1-alkyl group, it may contain an alkylene chain with 1 to 3, preferably 1, carbon atoms and preferably represents optionally substituted benzyl, in particular for 2- chlorobenzyl or 4-chlorobenzyl. When the group forming a biolabile ester represents an optionally substituted phenyl group, which phenyl ring is substituted with a lower alkylene chain, this may contain 3 to 4, and preferably 3, carbon atoms and, in particular, is indanyl. When the group forming a biolabile ester represents a C2.6 alkanoyloxy group of optionally substituted Ca-4 alkyl, the C2-6 alkanoyl group can be straight or branched chain. R1 preferably has the meanings of hydrogen, C? -4 -4 alkyl, p-methoxybenzyl, N, N-di- (C 0-4 alkyl) aminoC de _6 alkyl, (RS) -1- [[(isopropyl) carbonyl] -oxy] ethyl , (RS) -1- [[(ethyl) carbonyl] oxy] -2-methylpropyl, (RS) -1 - [[(cyclohexyloxy) carbonyl] oxy] -ethyl, 5-methyl-2-oxo-1, 3 -dioxolen-4-yl-methyl, 2-oxo-l, 3-dioxolan-4-yl-methyl or (RS) -1 - [[(ethoxy) carbonyl] oxy] ethyl. R2 preferably has the meanings of hydrogen, ethyl, methoxyethoxymethyl, (RS) -1 - [[(isopropyl) -carbonyl] oxy] ethyl, (RS) -1 - [[(ethyl) carbonyl] oxy] -2-methylpropyl , (RS) -1- [[(cyclohexyl i) carbonyl] oxy] ethyl, 5-methyl-2-oxo-l, 3-dioxolen-4-yl-methyl, 2-oxo-l, 3-dioxolan-4 -yl-methyl or (RS) -1- [[(ethoxy) carbonyl] oxy] ethyl. More preferred are the compounds that are selected from the group consisting of 2- [1- (1-carboxymethyl-2-oxo-2, 3,4,5-tetrahydro-1H-benzo [b] azepine] ethyl ester. -3-ylcarbamoyl) -cyclo-pentylmethyl] -4-phenyl-butyric [alternative name: 3- [l- (2'- (ethoxycarbonyl) -4'-phenylbutyl] -cyclopentan-1-carbonylamino] -2, 3 , 4,5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid of Formula II, 2- [1- (1-carboxymethyl-2-oxo-2, 3, 4, 5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-naphthalene-1-ethyl ester il-butyric [alternative name: acid 3- [l-. { 2- (Ethoxycarbonyl) -4- (1-naphthyl) butyl] cyclopentyl} carbonyl) amino] -2-oxo-2, 3,4,5-tetrahydro-lH-1-benzazepin-1-yl} acetic of Formula III, 2- [1- (1-carboxymethyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-phenyl-butyric acid of Formula IV , 2- [1- (1-Carboxymethyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [b] azepin-3-ylcarbomoyl) -cyclopentylmethyl] -4-naphthalene-1-yl-butyric acid Formula V, and physiologically compatible salts of the acids of Formulas II, III, IV and / or V. The compounds of Formulas II, III, IV and V are especially suitable in their 3S, 2'R forms. Most preferred is the compound of Formula II in its 3S, 2'R form, also known as "daglutril" or SLV306. The compounds of the Formula la are known, for example, from EP 0733642 Al, which is incorporated herein by reference and can be produced according to the production processes described or referenced herein or analogously to said processes of production. In addition, compounds of the general Formula Ib, wherein R1, R4 and R5 have the meanings given above, or physiologically compatible salts, of acids of Formula Ib can be used as double-acting compounds, capable of inhibiting NEP and the system that produces endogenous endothelin. The compounds of Formula Ib are known, for example, from EP 0916679 A1, which is incorporated herein by reference, and can be produced in accordance with the production processes described or referenced herein or analogously to said processes. production. Suitable R1 groups that form esters of biolabile carboxylic acids in compounds of Formula Ib are those specified for compounds of the formula above. Groups R4 and R5 suitable as groups forming biologically inactive phosphonic acid esters are those which can be separated under physiological conditions in vivo with release of the corresponding phosphonic acid functional group. For example, groups which are suitable for this purpose are lower alkyl groups, C2-C6 alkanoyloxy ethyl groups optionally substituted in the oxymethyl group with lower alkyl, or phenyl or phenyl-lower alkyl groups, which phenyl ring is optionally mono- or poly-substituted with lower alkyl, lower alkoxy or with a lower alkylene chain attached to two adjacent carbon atoms. If the group R4 and / or R5 which forms a biolabile ester is or contains lower alkyl, it may be branched or unbranched and may contain 1 to 4 carbon atoms. If R4 and / or R5 are an optionally substituted alkanoyloxymethyl group, they may contain a preferably branched alkanoyloxy group containing 2 to 6, and preferably 3 to 5, carbon atoms and may be, for example, a pivaloyloxymethyl radical (tert-butylcarbonyloxymethyl radical). ). If R 4 and / or R 5 are an optionally substituted phenyl-lower alkyl group, it may contain an alkylene chain containing 1 to 3, and preferably 1, carbon atoms. If the phenyl ring is substituted with a lower alkylene chain, it may contain 3 to 4, and in particular 3, carbon atoms and the substituted phenyl ring is, in particular, indanyl.

The compounds of Formula Ib contain a chiral carbon atom, primarily the carbon atom bearing the amide side chain at position 3 of the benzazepine structure. Thus, the compounds can be present in two optically active stereoisomeric forms or in racemate form. The present invention includes both racemic mixtures and isomerically pure compounds of Formula I. If R4 and R5 in compounds of Formula Ib are not hydrogen and in each case have different meanings, the phosphorus atom of the phosphonic acid group can also be chiral. The invention also relates to the isomeric mixtures and isomerically pure compounds of Formula Ib formed as a result of chiral phosphorus atoms. If compounds of Formula Ib are used according to the invention, (3- {[[1- (benzyloxy-ethoxy-phosphorylmethyl) -cyclopentanecarbonyl] -amino-tert-butyl ester is preferred. oxo-2, 3,4, 5-tetrahydro-benzo [b] azepin-1-yl) -acetic and the ester 1- [[1- (1-carboxymethyl] -2-oxo-2, 3,4, 5 -tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] - (1-isobutyryloxy-ethoxy) -phosphinoyloxy] -ethyl ester of isobutyric acid. Both compounds are particularly preferred if the stereochemistry at the chiral carbon atom (see above) is "S", mainly in its "(3S)" configuration.

The compounds of Formula Ib are known, for example, from EP 0916679 Al, and can be produced according to the production processes described or referenced herein or analogously to said production processes. Also preferred are compounds of the general Formula I, wherein R1, R6, R7 and R8 have the above meanings, and physiologically compatible salts of acids of the Formula I and / or physiologically compatible acid addition salts of compounds of the Formula I, for use as double-action compounds capable of inhibiting NEP and the system that produces endogenous endothelin, in pharmacological compositions according to the invention. The compounds of the Formula are known, for example, from WO 2005/030795 A1, which is incorporated herein by reference, and can be produced according to the production processes described or referenced herein or analogously to said processes. production processes. If in compounds of the formula I, the substituents R7 and / or R8 contain basic groups, in particular nitrogen, the compounds of the formula can also take place in the form of acid addition salts. Acid-containing, physiologically compatible salts of compounds of the formula are their conventional salts with inorganic acids, for example sulfuric acid, phosphoric acid or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example monocarboxylic, dicarboxylic or tricarboxylic acids lower aliphatics such as maleic acid, fumaric acid, tartaric acid, citric acid, or with sulfonic acids, for example, alkanesulfonic acids, such as methanesulfonic acid. Suitable R1 groups that form biolyable esters of carboxylic acids in compounds of the Formula are those specified for compounds of the Formula above. Suitable R6 groups that form biolabile carboxylic acid esters in compounds of the Formula are the same as those specified for groups R2 in compounds of the formula above. R7 preferably has the meanings hydrogen, methyl, ethyl, 2-hydroxyethyl, or 3-hydroxypropyl, each hydroxyl group being optionally esterified with C2-4 alkanoyl or an amino acid residue. If R8 has the meaning (C0-4 alkyl) 2 aminoalkyl of C? -6, one or two C0-4 alkyl groups may be present independently of one another. More specifically, "(C0-4 alkyl) 2-aminoalkyl of C? -6", expressly comprises the meanings "alkylamino of (Co) 2-alkyl of C? _6", "alkylamino of (C0) (C? - 4) -Ci-β alkyl "and" (C? _4) alkylamino-C--6-alkyl. "(C0) 2-C al--alkylamino" of Ci-β "is to designate an unsubstituted primary amino group (-NH2) bonded to alkyl (ene) of C? -6; "(C 1 -4) alkylamino-Ci-β alkyl" is to be referred to as a secondary amino group mono-substituted with Ci-4 alkyl and attached to C (-6 alkyl (ene), "" Alkylamino of (C? _4) 2-C? -6"alkyl is to denote a tertiary amino group disubstituted with C? _4 alkyl and attached to Ci_6 alkyl (ene) R8 preferably has the meanings isopropyl; methoxyethyl 2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group optionally being esterified with C2_4 alkanoyl or an amino acid residue, 3-acetoxy-n-propyl, cyclopropylmethyl, 2-methoxybenzyl, 4-methoxybenzyl, 4-methoxyphenylethyl, 2, - dimethoxybenzyl, 1-naphthylmethyl, 3-oxo-l, 1-dimethylbutyl, phenyl-2-oxoethyl, 2- (4-methoxyphenyl) -2-oxoethyl, 3- (2-oxoazepanyl), (C0-4) alkylamino -alkyl of C? -6, in particular dimethylamino-n-propyl, (methyl) aminoethyl, amino-n-propyl, amino-n-butyl or amino-n-pentyl. If R7 and R8 together are C4-7 alkylene whose methylene groups are optionally replaced or optionally substituted, in each case morpholine is preferred; piperidine; 4-cetopiperidine; 4-hydroxypiperidine, being optionally esterified with C2-4 alkanoyl or an amino acid residue in the hydroxyl group; piperazine or pyrrolidine. If, in the compounds of Formula I, hydroxyl groups are esterified with amino acid residues, these amino acid residues can be derived from natural or non-natural a- or b-amino acids. Suitable amino acids that can be used are chosen, for example, in the group consisting of alanine, 2-aminohexanoic acid (norleucine), 2-aminopentanoic acid (norvaline), arginine, asparagine, aspartic acid, cysteine, 3,4-dihydroxyphenylalanine (dopa), glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine (2, 5-diaminovaleric acid), 5-oxo-2-pyrrolidinecarbonic acid (pyroglutamic acid), phenylalanine, proline, serine, threonine, thyronine, trifophant, tyrosine and valine. Preferred amino acid residues are derived from alanine, asparagine, glutamine, glycine, isoleucine, leucine, lysine, ornithine, phenylalanine, proline and valine. The compounds of the Formula contain two chiral carbon atoms, mainly the carbon atom bearing the amide side chain in position 3 of the benzazepine skeleton (C *) and the carbon atom bearing the radical "-COOR6" (Ca) *) Thus, the compounds may be present in a total of four stereoisomeric forms. The present invention comprises mixtures of stereoisomers and enantiomers, and also the isomerically pure compounds of the Formula le. Preferably isomerically pure compounds of the Formula I are preferred. Particularly preferred are compounds of the Formula E in which the carbon atom carrying the amide side chain in position 3 of the benzazepine backbone is in the "S" configuration. With respect to the chiral carbon atom "Ca" bearing the radical "-COOR6", the configuration of the compounds of the Formula I that is preferred according to the invention in the context of this invention is provisionally assigned the designation of "rell" configuration. By analogous observations of appropriate compounds of known configuration, it can be derived that the preferred configuration "rell" in the chiral center "Ca *" is probably also the "S" configuration.

Particularly preferred compounds of the Formula are selected from the group consisting of: acid 2 { [1- ( { [1- (carboxymethyl) -2-oxo-2,3, 4,5-tetrahydro-lH-l-benzazepin-3-yl] amino} carbonyl) -5-cyclopentyl] methyl} -4- [isopropyl (methyl) amino] -4-oxobutanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5- + "~ *" '""' "'l-benzazepin-3-yl] amino.} - carbonyl) - H. "¿'cn1" 1 IGUCUJ-X * -4 - (dimethylamino) -4-oxobutanoic; ucioo 2- { [l- ( { [1- (carboxymethyl) -2-OXO -2, 3,4,5- .. 4J.a-. -_ri-1-zazepin-3-yl] amino.} Carbonyl) -cyclopentyl] methyl.} -4- (diethylamino) -4- oxobutanoic acid, 2- {[l- ( { [l- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino}. carbonyl) - 5-cyclopentyl] methyl.} -4- [(2-hydroxyethyl) (methyl) amino] -4-oxobutanoic acid: 2 { [1- ( { [1- (carboxymethyl) -2- oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino.} carbonyl) -cyclopentyl] methyl.} -4- [(3-hydroxypropyl) (methyl) amino] - 4- 0 oxobutanoic acid 2- { [L- ( { [1- (carboxymethyl) -2-OXO-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino .}. carbonyl) -cyclopentyl] methyl.} -4- (4-hydroxy-piperidin-1-yl) -4-oxobutanoic acid; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2,3,, 5-tetrahydro-lH-l-benzazepin-3-yl] amino.} carbonyl) -cyclopentyl] methyl} -4-oxo-4- [4- (L-valyloxy) piperidin-1-yl] butanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2,3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino.} carbonyl) -cyclopentyl] methyl} -4-morpholin-4-yl-4-oxobutanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino.} carbonyl) -cyclopentyl] methyl} -4-oxo-4- (4-oxopepyridin-1-yl) butanoic; 4 [bis (2-hydroxyethyl) amino] -2- acid. { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino} carbonyl) cyclopentyl] methyl} -4-oxobutanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-1] amino.} Carbonyl) -cyclopentyl] methyl} -4- . { ethyl [3- (ethylamino) propyl] amino} -4-oxobutanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino.} Carbonyl) -cyclopentyl] methyl} -4- [[2- (dimethylamino) ethyl] (methyl) amino] -4-oxobutanoise- 4- [(3-aminopropyl) (ethyl) amino] -2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-benzazepin-3-yl] amino.} Carbonyl) cyclopentyl] methyl} -4-oxobutanoic; 2- acid. { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin-3-yl] amino.} Carbonyl) -cyclopentyl] methyl} -4- (Methyl [2- (methylamino) ethyl] amino} -4-oxobutanoic acid, 4- [(4-aminobutyl) (methyl) amino] -2-. {[[L- ( { [ 1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-1-benzazepin-3-yl] amino.} Carbonyl) cyclopentyl] methyl.} -4-oxobutanoic acid 4- [(4-aminobutyl) (ethyl) amino] -2- { [L- ( { [1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-lH-l-benzazepin -3-yl] amino.} Carbonyl) cyclopentyl] methyl.} -4-oxobutanoic acid 2- ([1- ( { [1- (carboxymethyl) 2-oxo-2, 3,4,5 -tetrahydro-lH-l-benzazepin-3-yl] amino.} carbonyl) -cyclopentyl] methyl.} -4- (methyl [3- (methylamino) propyl] amino.} -4-oxobutanoic acid and - [(5-aminopentyl) (methyl) amino] -2- { [1- ( { [1- (carboxymethyl) -2-oxo-2, 3,4, 5-tetrahydro-lH-1- benzazepin-3-yl] amino.} carbonyl) cyclopentyl] methyl.} -4-oxobutanoic, together with their biologically inactive esters and physiologically compatible salts of acids of these compounds of the formula I and / or salts by addition of physiologically compatible acids of these compounds of the Formula le. ATi receptor antagonists are pharmacologically active drug compounds which are capable of selectively blocking the ATi subtype of the angiotensin II receptor in mammals and humans and which are known to possess, for example, antihypertensive properties. ATX receptor antagonists that can be used in accordance with the present invention can be chosen from the group consisting of abitesartan, benzylosertan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycylosertan, irbesartan, isoteoline, losartan, milfasartan , olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 057, Lusofarmaco LR-B / 081, Lusofarmaco LR-B / 087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP- 6803, EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KW-3433, L-158809, L-158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY- 301875, LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM -31472, ZD-6888, ZD-7155 and ZD-8731, which are all known per se, or any salts, solvates, prodrugs os or their physiologically compatible esters. Preferred ATi receptor antagonists are chosen from the group consisting of abitesartan, benzylosertan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycylosertan, irbesartan, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, tasosartan , tel isartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 081, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247 or any salts, solvates, prodrugs or their physiologically compatible esters. Candesartan, eprosartan and losartan are the most preferred ATi receptor antagonists. Eprosartan is usually used in the form of its mesylate. Losartan is used, usually, in the form of losartan-potassium. Candesartan is used, usually, in the form of candesartan cilexetil. Additional pharmaceutical compositions that can be favorably used in the treatment and / or prophylaxis of cardiovascular conditions or diseases comprise pharmacologically effective amounts of each of: a) at least one NEP inhibitor as the first active agent, b) at least one inhibitor of the system which produces endogenous endothelin as the second active agent, and c) at least one classic cardiovascular drug as a third or additional active agent. Appropriate classical cardiovascular drugs can be chosen from the group consisting of non-selective alpha-adrenoceptor antagonists, for example tolazoline or phenoxybenzamine; selective alpha-adrenoceptor antagonists, for example doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, for example acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; mixed alpha- and beta-adrenoceptor antagonists, for example carvedilol or labetolol; ganglion blockers, for example, reserpine or guanethidine; alpha2-adrenoceptor agonists (including alpha2-adrenoceptor agonists that act centrally), for example clonidine, guanfacine, guanabenz methyldopa and moxonidine; renin inhibitors, for example alskiren; ACE inhibitors, for example benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; mixed or selective antagonists of the endothelin receptor, for example atrasentan, bosentan, clazosentan, darusentan, sitaxsentan, tezosentan, BMS-193884 or J-104132; direct vasodilators, for example diazoxide, dihydralazine, hydralazine or minoxidil; mixed ACE / NEP inhibitors, for example omapatrilat; ECE inhibitors, for example FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; selective NEP inhibitors; vasopressin antagonists, aldosterone receptor antagonists, e.g. eplerenone; angiotensin vaccine; and urotensin II receptor antagonists. Preferably, classical cardiovascular drugs should be administered together with a drug selected from the group consisting of 2- [1- (1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H- ethyl) ethyl ester. benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-phenyl-butyric; 2- [1- (1-carboxymethyl-2-oxo-2, 3,4,5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-naphthalene-1-ethyl ester il-butyric; 2- [l- (l-carboxymethyl-2-oxo-2, 3,4,5-tetrahydro-lH-benzo [b] azepin-3-carbamoyl) -cyclopentylmethyl] -4-phenyl-butyric acid; 2- [l- (l-carboxymethyl-2-oxo-2, 3,4, 5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-naphthalen-1-yl-butyric acid; and their physiologically compatible salts. More preferably, classical cardiovascular drugs should be administered together with daglutril. The pharmaceutical compositions according to the invention can be prepared in a manner known per se and, therefore, can be obtained in the form of formulations suitable for enteral, such as oral or rectal, or parenteral administration to mammals or humans, comprising an amount Therapeutic efficacy of the pharmacologically active agents, alone or in combination with one or more pharmaceutically acceptable excipients and / or excipients, especially suitable for enteral or parenteral application. Pharmaceutical compositions for enteral or parenteral administration are, for example, in unit dosage forms, such as coated tablets, lozenges, capsules or suppositories and, also, ampoules. These are prepared in a manner known per se, for example, using conventional mixing, granulating, coating, dissolving or lyophilizing processes. Typical oral formulations include coated tablets, lozenges, capsules, syrups, elixirs, and suspensions. The capsules may contain the active agents, for example, in the form of powders, granules, pills, beads, or micropacks. For example, a pharmaceutical composition according to the invention may consist of between about 0.1% and 90%, and preferably from about 1% to about 80%, of the active agents, the remainder being formed by pharmaceutically auxiliary substances and / or excipients. acceptable Therefore, pharmaceutical compositions for oral use can be obtained by combining the active compounds with solid excipients, if it is desired to granulate a mixture that has been obtained and, if required or needed, to elaborate the mixture or granulate into cores of coated tablets or lozenges. , after having added appropriate auxiliary substances. Typical injectable formulations include solutions and suspensions. In one embodiment of the pharmaceutical compositions according to the invention, the active agents (a), (b) and (c) can be obtained and administered together, for example, in the form of a combined unit dose such as a tablet or capsule, that is, in a physical combination. In such a combined unit dose form, the different active agents (a), (b) and (c) can be separated from one another, for example by means of different compartments in said capsule, for example by the use of intermediate inert layers known in the art; or by means of different compartments in said capsule (ie compartmentalized). The corresponding active agents or their pharmaceutically acceptable salts can also be used in the form of their hydrates or include other solvents used for crystallization. A unit dosage form can be a fixed combination. A unit dosage form, in particular a fixed combination of the active agents (a), (b) and (c) is a preferred alternative of this embodiment. Fixed combinations comprising daglutril and eprosartan, daglutril and candesartan or daglutril and losartan are preferred embodiments of the invention. In another modality, the active agents (a), (b) and (c) can be obtained and administered in two or more separate unit dose forms, for example, in two or more tablets or capsules, the tablets or capsules being physically separated from one another. The two or more separate unit dosage forms can be administered simultaneously or gradually (separately), for example sequentially one after the other, in any order. Therefore, the active agents can be administered in any order at the same time or at different times distributed throughout the day, usually determining the optimum dosage regime by prescription of the doctor. If a double-acting compound capable of inhibiting NEP and the system that produces endogenous endothelin is used to encompass the combination of active agents (a) and (b), the active agents [(a) + (b)] and (c) in the pharmaceutical composition they may be favorably present in two separate dosage forms, usually complementary or balanced for combined use, for example in the form of two different pills or capsules, which usually also comprise pharmaceutically acceptable auxiliary substances and / or carriers, or in compartments different from a single capsule. Thus, in this embodiment, at least the ATi receptor antagonist is present in the form of a dose of a single unit physically separated from the other or other active agents. The typical pharmaceutically acceptable excipients and / or excipients described above are illustrated by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives such as carboxymethylcellulose, ethylcellulose and sodium methylcellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth stearates such as magnesium stearate and calcium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; beta-cyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other fillers, binders, non-toxic compatible disintegrators, agents such as talc; buffers, preservatives, antioxidants, lubricants, flavorings, and the like commonly used in pharmaceutical formulations. In a specific embodiment of said first aspect, the invention also relates to a kit (kit) comprising, in separate containers in a single container, pharmaceutical dosage forms for use in combination, comprising, il) in a separate container, a pharmaceutical dosage form comprising, at least one neutral endopeptidase inhibitor and in a second separate container, a pharmaceutical dosage form comprising, at least one inhibitor of the system producing endogenous endothelin, or i2) in a separate container, a pharmaceutical dosage form comprising a double-acting compound capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system; and ii) in a separate container, a pharmaceutical dosage form comprising at least one ATi receptor antagonist. The case form is particularly advantageous but not limited to the case when the separate components must be administered in different dosage forms or administered at different dosage intervals. Dosage forms may be favorably oral formulations such as pills or capsules. Separate containers may be, for example, blister packs, particularly when the oral formulations are coated tablets or chips, boxes or other containers commonly used for packaging pharmaceutical dosage forms. Preferred are alternatives to the kit comprising, in a separate container, a pharmaceutical dosage form comprising a double-acting compound capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system, and in a separate container a pharmaceutical dosage form comprising , at least one ATi receptor antagonist. The kit can also include brochures or other written instructions on how to best use the different constituents of the kit to achieve the best therapeutic results with the combination of active ingredients. In a second aspect, the invention also relates to a use of at least one NEP inhibitor in combination with at least one inhibitor of the endogenous endothelin producing system and at least one ATi receptor antagonist for the preparation of a composition pharmaceutical or medicament for the prophylaxis or treatment of a cardiovascular disease, in particular hypertension and / or heart failure; essential hypertension and / or pulmonary hypertension in animals and humans. In a third aspect, the invention relates to a method for treating or preventing a cardiovascular disease in mammals and humans, comprising administering to an individual in need, an effective amount of a combination of, at least one NEP inhibitor, at least one inhibitor of the endogenous endothelin producing system and at least one ATX receptor antagonist. Individuals in need of such treatments are, in particular, humans or mammals that are suffering or are susceptible to heart disease, in particular hypertension and / or heart failure; essential hypertension and / or pulmonary hypertension. In addition, the combination treatment according to the present invention is also considered, appropriate or beneficial for the treatment and / or prevention of endothelial dysfunction and / or sexual dysfunction, in particular malfunction in males, and more particularly erectile dysfunction. The active agents (a), (b) and (c) can be obtained and administered together, sequentially one after the other or separately in a unit dose form, combined, for example, in a tablet or capsule. Therefore, the active agents can be administered in any order at the same time and at different times spaced throughout the day, usually determining the optimum dosage regime by prescription of a doctor. In a specific embodiment of said third aspect, a fixed combination of a double-acting compound, capable of inhibiting neutral endopeptidase and the endogenous endothelin production system, and an ATX receptor antagonist can be used. Fixed combinations comprising daglutril and eprosartan, daglutril and candesartan or daglutril and losartan are preferred alternatives of this specific modality.

Description of pharmacological test methods The beneficial effects of the combination therapy according to the invention can be presented, for example, in a clinical trial protocol and in an animal model in rats: Clinical trial protocol A single-dose study in several randomized, parallel-group, placebo-controlled centers of oral daglutril (see above) was conducted for 12 hours of catheterization of the right side of the heart in humans with congestive heart failure ( CHF). Each individual received a dose of daglutril or placebo. The study consisted of three visits (or study days when individuals were included). The outpatients were in the hospital for two nights and one day. The criteria for evaluation efficacy were systemic vascular resistance (SVR), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) volume, cardiac rhythm (HR), pulmonary and systemic systolic, diastolic and mean pressures; pulmonary vascular resistance (PVR); heart rate index (SVI); cardiac index (Cl); transpulmonary gradient and neurohormones. The primary efficacy parameter was the maximum decrease from baseline over 6 hours for SVR and was compared between treatment groups using covariance analysis, with baseline value as covariate and center and NYHA classification as factors . The trial unilaterally developed at a total significance level of a = 0.05. The artifact fit for multiple comparisons was controlled by applying Dunnett's procedure. In addition, the existence of a dose-response relationship for daglutril was evaluated by investigating linear, quadratic and cubic contrasts. The secondary efficacy parameter was the maximum change from the baseline for PCWP and was analyzed in the same way as the primary variable. The maximum decrease from the baseline over 12 hours, the change for each individual time point and the area adjusted under the curve (AUC) for 6 and 12 hours, were analyzed for SVR and PCWP, using similar statistical methodology for the main parameter of interest. All other tertiary efficacy parameters were analyzed using the same statistical methodology as for the primary efficacy parameter. The criteria for assessing safety were laboratory variables; electrocardiogram (ECG); physical exams; vital signs and adverse events (AEs). The criteria for inclusion included male or female individuals (without maternity potential), aged = 18 to 85 years, with a history of chronic, symptomatic, mild to severe CHF (NYHA Class II-IV) for at least three months, with documented systolic dysfunction [left ventricular ejection fraction (LVEF) = 35% by echocardiography] who received a stable dose of their individually optimized medication regimen for at least one week before enrolling in the study. (96) Individuals were selected and (75) were randomized and analyzed, (18) individuals in the 200 mg daglutril group, (20) individuals in the daglutril 400 mg group, (19) individuals in the 800 mg daglutril group and (18) individuals in the placebo group. In a subgroup analysis, the 75 individuals randomly chosen in the study were divided into subgroups, mainly placebo or daglutril, with present or absent criteria. As a criterion, it was taken if the concomitant losartan-potassium medication was taken before, and continued after, the randomization. In the placebo group, 1 patient took losartan-potassium, while 15 patients did not take losartan-potassium. In the daglutril group, 5 patients took losartan-potassium, while 49 patients did not take losartan-potassium. Statistical summary data of the mean are given during the first 6 hours (0.5, 6 hours, only computed if none of the time points have lost data) (average, standard deviation (SD), n). For subgroups of present or absent criteria, the corrected mean values of placebo and summary statistical data are given [mean change, standard error of change (SE) and standardized mean change (mean / SE)]. In this trial model, the administration of daglutril in addition to a concomitant medication with an ATi receptor antagonist (losartan) before and after randomization, respectively, presented the results, on mean change corrected for placebo, of the mean pressure pulmonary artery (MPAP; 0.5-6 hours) given in Table 1 below: Table 1: Pharmacological results of co-administration of daglutril and ATi receptor antagonist (losartan-potassium) on MPAP The test results demonstrate that the beneficial influence on pulmonary blood pressure of a double-acting compound, capable of inhibiting NEP and the endogenous endothelin-producing system, mainly daglutril, in addition to an ATi receptor antagonist, was relatively more marked than influence that resulted from the administration of a double action compound to inhibit NEP and the endogenous endothelin producing system, mainly daglutril, alone.

Test model with animals Male rats, spontaneously hypertensive (SHR, Charles River's insulin resistant class, 6 months old) were equipped with telemetry transmitters for continuous monitoring of blood pressure and heart rate (as described below). After 3 days of control under baseline conditions (untreated), the animals were divided into two groups receiving an ATi receptor antagonist (eprosartan mesylate, hereinafter referred to as experiment I, or candesartan cilexetil, referred to as the next experiment II) or an antagonist of the ATi receptor plus daglutril in combination. In experiment II, a third group of rats was included, receiving only daglutril. The compounds were administered via drinking water, and the daily intake of medication was measured by weighing the bottles of water three times a week. The daily doses intended in experiment I were 60 mg / kg / day of eprosartan mesylate plus, in the combination group, 100 mg / kg / day of daglutril. In experiment II, the intended daily doses were 1 mg / kg candesartan cilexetil, and 100 mg / kg daglutril in daglutril alone and the combination group. Telemetry transmitters for continuous control of blood pressure, heart rate and locomotor activity (TA11PA-C40, Data Sciences, USA) were implanted intraabdominally with inhalative halothane anesthesia. An abdominal incision was made in the midline, and the abdominal aorta was visualized by separation of the retroperitoneal fat and connective tissue. A ligature was placed caudal to the renal arteries, the aorta was punctured with a 22G needle and the catheter was introduced into the interior of the aorta. The entry site was closed with adhesive tissue (Vetbond®, 3M, USA), the ligature was separated, and the abdominal incision was closed. Measurements of aortic pressure were taken every 5 minutes for 4 seconds, each at a sampling rate of 500 Hz, and corrected for the corresponding ambient pressure (ambient pressure monitor, C11PR, Data Sciences, USA). Concentrations of receptor antagonists ATi and daglutril in the drinking water were adjusted once a week, in order to guarantee the intended daily intake. In experiment I, the average daily water intake over the 33-day treatment period amounted to 51 and 56 ml / kg in eprosartan and in the eprosartan plus daglutril group, respectively, which resulted in the intake of 62 mg / kg / day of eprosartan in both groups, and 104 mg / kg / day of daglutril in the combination group. In experiment II, the average daily intake of water during the 25-day treatment period was 64 ml / kg (candesartan only), 62 ml / kg (daglutril only) and 62 ml / kg (candesartan plus daglutrin), giving as a result, daily doses of candesartan 0.9 mg / kg, both in the candesartan group and in the combination group, and 101 mg / kg and 98 mg / kg daglutril in the daglutril group and in the combination group, respectively . Blood pressure, heart rate and activity values, measured at 5 minute intervals by the Dataquest system, were used to calculate individual means of 24 hours. These 24-hour averages were taken to Excel, and the mean values of the systolic blood pressure (SBP) and diastolic blood pressure (DBP) groups, heart rate (HR) and locomotor activity (ACT) were calculated for the different treatment groups. For the statistical analysis, a baseline (pre) value was calculated from 3 days before the application of the compound, and the effects of the ATi receptor antagonist, daglutril and its combination were calculated in relation to this line value of base (average value during a treatment period minus the value of the baseline). The statistical comparison was made using analysis of variance, followed by the Student's t-test for comparison of the ATX receptor antagonist and combination groups, both with an error level of P <; 0.05.In this test model, the administration of daglutril, alone and in combination with an ATI receptor antagonist (eprosartan mesylate or candesartan cilexetil), and compared to the administration of ATi receptor antagonist alone, showed the results given in the Tables 2 and 3 below: Table 2: Effects of coadministration of daglutril and ATX receptor antagonist (eprosartan mesylate) on cardiovascular parameters in spontaneously hypertensive rats Changes are presented versus equalized baseline values, measured before the start of treatment; n = 5 animals per group; SEM = Standard Measurement Error, bilateral ANOVA, n.s = not significant, bilateral t test of eprosartan versus eprosartan + daglutril with * P < 0.05, (1) data from experiment II.

Table 3: Effects of Coadministration of Daglutril and ATi Receptor Antagonist (Candesartan Cilexetil) on Cardiovascular Parameters in Hypertensive Rats Spontaneously Changes are presented versus equalized baseline values, measured before the start of treatment; n = 5 animals per group; Bilateral ANOVA; n.s = not significant; bilateral t-test of candesartan versus candesartan + daglutril with * P < 0.01.

In both experiments, the decrease in systolic blood pressure was significantly greater in the combination group (t test, P <0.05), than in the group that received the respective ATi receptor antagonist alone. In addition, daglutril, when given alone, did not result in blood pressure reduction in this model. The dosage of the active agents may depend on a variety of factors, such as mode of administration, species, age and / or individual condition. Appropriate dosages of the active agents of the pharmaceutical combination according to the present invention are therapeutically effective doses, for example those that are commercially available. Normally, in case of oral administration, an approximate daily dose of between approximately 4 mg and approximately 600 mg is to be estimated for each of the active agents, for example for a patient of approximately 75 kg in weight. For example, a pharmaceutical composition according to the invention should preferably comprise daglutril as a double action compound capable of inhibiting ECE and hSEP in the range of 5-600 mg. The range of doses of ATi receptor antagonists that are present in the pharmaceutical compositions according to the invention may vary depending, inter alia, on the substance used and may be (each calculated by the pure active substance, not its salt or solvate), for example, 4-32 mg for candesartan, 300-600 mg for eprosartan, 75-300 mg for irbesartan, 25-100 mg for losartan, 20-80 mg for telmisartan or 40-320 mg for valsartan. The administration of the pharmaceutical composition can take place up to three times a day. Forms of once-a-day administration are preferred.

Example I: Capsules containing daglutril and losartan: Capsules are produced with the following composition per capsule: Tricalcium phosphate salt Daglutril 200 mg Losartan-potassium 50 mg Corn starch 50 mg Lactose 80 mg Ethyl acetate c.s.

The active agents, corn starch and lactose were processed in a homogeneous slurry, using ethyl acetate. The pulp was milled and the resulting granules were placed in an appropriate tray and dried at 45 ° C in order to remove the solvent. The dried granules were passed through a crusher and mixed in a mixer with the following additional auxiliaries: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then poured into 400 mg capsules (capsule size 0).

Claims (21)

1. Pharmaceutical composition, comprising pharmaceutically effective amounts, of each of: a) at least one NEP inhibitor; b) at least one inhibitor of the endogenous endothelin producing system, and c) at least one ATi receptor antagonist.

2. The pharmaceutical composition according to claim 1, further comprising at least one pharmaceutically acceptable auxiliary substance and / or excipient.

3. Pharmaceutical composition according to claim 1, further comprising acetylsalicylic acid.

4. The pharmaceutical composition according to claim 1, wherein said composition comprises an administrable dosage form selected from the group consisting of tablets, coated tablets, capsules, syrups, elixirs or suspensions.

5. The pharmaceutical composition according to claim 1, wherein at least the ATi receptor antagonist is present in a single unit dosage form, physically separated from the NEP inhibitor and the inhibitor of the endogenous endothelin producing system.

6. The pharmaceutical composition according to claim 1, wherein the inhibitor of the endogenous endothelin producing system is selected from the group consisting of inhibitors of enzyme that is converted into endothelin, inhibitors of human soluble endopeptidase and double-acting compounds capable of inhibiting enzyme that is converts to endothelin and human soluble endopeptidase.

7. The pharmaceutical composition according to claim 1, comprising as a sub-combination of at least one neutral endopeptidase inhibitor (a) and at least one inhibitor of the endogenous endothelin-producing system (b), a double-acting compound capable of inhibiting neutral endopeptidase and the system endogenous endothelin producer.

8. Pharmaceutical composition according to claim 7, comprising as a sub-combination of at least one inhibitor (a) of neutral endopeptidase and, at least one inhibitor of the endogenous endothelin-producing system (b), a double-acting compound capable of inhibiting neutral endopeptidase and endopeptidase soluble human.

9. Pharmaceutical composition according to claim 7 or 8, wherein said double-acting compound, capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system, is a compound of general Formula I, wherein: R1 is hydrogen or a group that forms a biolabile ester of carboxylic acid; A represents a group chosen in subgroups (a), R3 wherein: R is hydrogen or a group that forms a biolabile carboxylic acid ester; and R 3 is a phenyl-C 4 alkyl group which may optionally be substituted on the phenyl ring with C 4 -4 alkoxy C 4 alkyl or halogen; or a naphthyl-C-alkyl group or (b), R50 / ^ R'O wherein: R4 is hydrogen or a group that forms a biolabile ester of phosphonic acid, and R5 is hydrogen or a group that forms a biolabile phosphonic acid ester; or (c) wherein: R6 is hydrogen or a group that forms a biolabile carboxylic acid ester; R7 is hydrogen, C? -4 alkyl or C? - hydroxyalkyl, whose hydroxyl group is optionally esterified with C2.4 alkanoyl or an amino acid residue, and R8 is C? -4 alkyl; C.sub.4-4 alkoxy of C.sub.1 - alkyl; hydroxyalkyl of C? -, which is optionally substituted with a second hydroxyl group and whose hydroxyl groups are each optionally esterified with C2-4 alkanoyl or an amino acid residue; (C 0 -) alkyl 2-aminoalkyl of Ci-β; C3-7 cycloalkyl; C3 cycloalkyl - C? - alkyl; phenyl-C 1 -4 alkyl, which phenyl group is optionally substituted 1-2 times with C 1 alkyl, C 1 alkoxy and / or halogen; Naphthyl-C 4 alkyl; C3-6 oxoalkyl, - phenylcarbonylmethyl, whose phenyl group is optionally substituted 1-2 times with C? -4 alquilo alkyl, C? -4 alco and / or halogen alkoxy, or 2-oxoazepanyl, or R7 and R8 together are alkylene of C4_, whose methylene groups are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and / or sulfur and which are optionally substituted once with hydroxyl, which is optionally esterified with C2_4 alkanoyl or an amino acid residue; Ci-4 alkyl; hydroxyalkyl of C? -4, whose hydroxyl group is optionally esterified with C2-4 alkanoyl or an amino acid residue; phenyl or benzyl; or a physiologically compatible salt thereof

10. The pharmaceutical composition according to claim 9, wherein said double-acting compound, capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system, of the general Formula la, wherein R1 is hydrogen or a group that forms a biolabile carboxylic acid ester; R2 is hydrogen or a group that forms a biolabile carboxylic acid ester; and R3 is a phenyl-C4-4 alkyl group which may optionally be substituted on the phenyl ring with C1-4alkyl, C4-4alkoxy or halogen; or a naphthyl-C de -4 alkyl group; or a physiologically compatible salt thereof.

11. The pharmaceutical composition according to claim 10, wherein the double-acting compound, capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system is selected from the group consisting of: 2- [1- (1-carboxymethyl-) ethyl ester 2-oxo-2, 3,4, 5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-phenyl-butyric acid ethyl ester 2- [1- (l-carboxymethyl- 2-oxo-2, 3,4, 5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-naphthalene-l-yl-butyric, 2- [l- (l-carboxymethyl -2-oxo-2, 3,4,5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-phenyl-butyric acid, 2- [1- (l-carboxymethyl-2- oxo-2, 3,4,5-tetrahydro-lH-benzo [b] azepin-3-ylcarbamoyl) -cyclopentylmethyl] -4-naphthalen-1-yl-butyric, and the physiologically compatible salts of any of the foregoing.

12. The pharmaceutical composition according to claim 9, wherein said double-acting compound, capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system is a compound of the general Formula I, wherein: R6 is hydrogen or a group that forms a biolabile ester; R7 is hydrogen, C? _4 alkyl or C? -4 hydroxyalkyl, whose hydroxyl group is optionally esterified with C2- alkanoyl or an amino acid residue; and R8 is C? -4 alkyl; C 4 -4 alkoxy of C 4 -4 alkyl; hydroxyalkyl of C? -4, which is optionally substituted with a second hydroxyl group and whose hydroxyl groups are each optionally esterified with C2-4 alkanoyl or an amino acid residue; (C0-4 alkyl) 2-C 1-6 aminoalkyl; C3-7 cycloalkyl; C3-7 cycloalkyl-C? -4 alkyl; phenyl-C 1 -4 alkyl, which phenyl group is optionally substituted 1-2 times with C? -4 alquilo alkyl, C? _4 alkoxy and / or halogen; Naphthyl-C? -4 alkyl; C3-E oxoalkyl; phenylcarbonylmethyl, whose phenyl group is optionally substituted 1-2 times with C? -4 alquiloalkyl, C ?- and / or halogen, or 2-oxoazepanyl; or R7 and R8 together are C4 alkylene. , whose methylene groups are optionally replaced 1-2 times with carbonyl, nitrogen, oxygen and / or sulfur and which are optionally substituted once with hydroxyl, which is optionally esterified with C2_4 alkanoyl or an amino acid residue; C? -4 alkyl; hydroxyalkyl of C? -4, whose hydroxyl group is optionally esterified with C2- alkanoyl or an amino acid residue; phenyl or benzyl; or a physiologically compatible salt thereof.

13. The pharmaceutical composition according to claim 12, wherein in the compound of the formula le, R7 is hydrogen, methyl, ethyl, 2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group being optionally esterified with C2-4 alkanoyl or a residue of amino acid

14. Pharmaceutical composition according to claim 12, wherein in the compound of the Formula le, R8 is isopropyl; methoxyethyl; 2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group being optionally esterified with C2_4 alkanoyl or an amino acid residue; 3-acetyloxy-n-propyl; cyclopropylmethyl; 2-methoxybenzyl, 4-methoxybenzyl; 4-methoxyphenylethyl; 2,4-dimethoxybenzyl; 1-naphthylmethyl; 3-oxo-l, 1-dimethylbutyl; phenyl-2-oxoethyl; 2- (4-methoxyphenyl) -2-oxoethyl; 3- (2-oxoazepanyl); (C0-4 alkyl) 2-aminoalkyl of C? -6, in particular dimethylamino-n-propyl, (methyl) aminoethyl, amino-n-propyl, amino-n-butyl or amino-n-pentyl.

15. Pharmaceutical composition according to claim 1, wherein the ATI receptor antagonist is selected from the group consisting of abitesartan, benzylosertan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycylosartan, irbesartan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 057, Lusofarmaco LR-B / 081, Lusofarmaco LR B / 087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A -81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE -3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803 , EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KW-3433, L-158809, L -158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875 , LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U -96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM- 31472, ZD-6888, ZD-7155 and ZD-8731.

16. Pharmaceutical composition according to claim 1, wherein the ATi receptor antagonist is selected from the group consisting of abitesartan, benzylosertan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycylosetan, irbesartan, losartan, milfasartan, olmesartan. , opomisartan, pratosartan, ripisartan, saprisartan, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 081, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247 or any salts, solvates, prodrugs or their physiologically compatible esters.

17. Pharmaceutical composition according to claim 1, wherein the ATi receptor antagonist is candesartan, eprosartan or losartan.

18. Use of at least one neutral endopeptidase inhibitor in combination with at least one inhibitor of the endogenous endothelin producing system and at least one ATi receptor antagonist for the preparation of a medicament for the prophylaxis or treatment of a cardiovascular disease in mammals and humans .

19. Use according to claim 18, wherein the cardiovascular disease is selected from the group consisting of essential hypertension, pulmonary hypertension and congestive heart failure.

20. Case or kit comprising, in separate containers, in a single package, pharmaceutical dosage forms for use in combination, comprising, il) in a separate container, a pharmaceutical dosage form comprising at least one neutral endopeptidase inhibitor and in a second separate container a pharmaceutical dosage form comprising at least one inhibitor of the endogenous endothelin producing system; or i2) in a separate container, a pharmaceutical dosage form comprising a double-acting compound capable of inhibiting neutral endopeptidase and the endogenous endothelin-producing system; and ii) in a separate container, a pharmaceutical dosage form comprising at least one ATi receptor antagonist.

21. A kit according to claim 20, comprising, in separate containers in a single package, pharmaceutical dosage forms for use in combination, comprising: i) in a separate container, a pharmaceutical dosage form comprising a double action compound capable of inhibit neutral endopeptidase and the endogenous endothelin producing system; and ii) in another separate container, a pharmaceutical dosage form comprising at least one ATi receptor antagonist.