AU2005256634B2 - Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and AT1-receptor antagonists - Google Patents

Description

WO 2006/000564 PCT/EP2005/052915 Solvay Pharmaceuticals GmbH 30173 Hannover Pharmaceutical Compositions Comprising NEP-Inhibitors, Inhibitors of the Endogenous Endothelin Producing System and

AT

1 Receptor Antagonists The present invention relates to a novel combination therapy for cardiovascular dis eases, in particular essential hypertension, pulmonary hypertension and/or congestive heart failure, by a synergistic combination of at least one inhibitor of neutral endopepti dase (= NEP), at least one inhibitor of the endogenous endothelin producing system and at least one AT 1 receptor antagonist. Thus, the invention also relates to novel pharma ceutical compositions comprising NEP inhibitors, inhibitors of the endogenous endothelin producing system and AT 1 receptor antagonists and the use of said pharmaceutical com position in the prophylaxis or treatment of cardiovascular diseases in mammals and hu mans. The nature of cardiovascular, in particular hypertensive vascular, diseases is multi factorial. Combination therapy has been shown to address the multiple pathophysiologic factors that play a role in blood pressure elevation, including blood volume, vasoconstric tion, and the impact of sympathetic nervous system and Renin-Angiotensin-Aldosterone System (= RAAS) activity (see e.g. M.R. Weir, American Journal of Hypertension 11 (1998) 163S-169S), potentially resulting in both greater reduction in blood pressure and in lowered risks for target-organ damage. The use of a fixed, low-dose combination agent could also offer lower doses of each component than those that may be necessary with monotherapy, thus reducing the risks of dose-dependent adverse events and asso ciated compliance problems. From document EP 0 254 032 A2 it is known that NEP inhibitors can lower blood pressure under conditions where angiotensin converting enzyme (= ACE) inhibitors as a monotherapy are relatively ineffective. Further, this document discloses that NEP inhibi tors may be combined with other drugs used in the treatment of hypertension, e.g. ACE inhibitors, to enhance the effects of those drugs. Consequently, pharmaceutical composi tions comprising both a NEP inhibitor and an ACE inhibitor are described. Document WO 03/059345 Al provides pharmaceutical compositions comprising a specific AT 1 receptor antagonist, valsartan, and NEP inhibitors for the treatment or pre vention of inter alia cardiovascular diseases.

WO 2006/000564 PCT/EP2005/052915 2 Although the beneficial role of NEP inhibiting compounds in the treatment or pre vention of cardiovascular diseases, in particular essential hypertension, pulmonary hy pertension and/or congestive heart failure, is widely acknowledged today, their profile of action is still suffering from certain inherent deficiencies. In congestive heart failure, as a result of the decreased cardiac output and the increase in peripheral resistance, back pressure phenomena of the blood occur in the pulmonary circulation and the heart itself. As a result, an increased wall tension of the heart muscle occurs in the area of the auri cles and chambers. In such a situation, the heart functions as an endocrine organ and secretes, inter alia, the atrial natriuretic peptide (= ANP) into the bloodstream. Due to its marked vasodilatory and natriuretic/diuretic activity, ANP brings about both a reduction in the peripheral resistance and a decrease in the circulating blood volume. The conse quence is a marked pre- and afterload decrease. This constitutes an endogenous car dioprotective mechanism. This positive endogenous mechanism is limited in that ANP has only a very short half-life in the plasma. The reason for this is that the hormone is very rapidly broken down by NEP. Therefore, pharmacological NEP inhibition rises ANP levels and thus promotes this cardioprotective mechanism. In congestive heart failure, due to a disease-related reduced output of the heart, a reflex increase in peripheral vascular resistance occurs. As a result, the heart muscle must begin to pump against an increased afterload. In a vicious cycle, this results in increased strain on the heart and worsens the situation further. The increase in the peripheral resistance is mediated, inter alia, by the vasoactive peptide endothelin. Endothelin (= ET) is the strongest presently known endogenous vasoconstrictory substance and is formed from the precursor big endothelin (= bigET) with participation of the endothelin converting enzyme (= ECE). NEP is involved not only in the breakdown of ANP but also in the breakdown of endothelin. For these reasons, a combination of compounds having NEP-inhibiting activity with compounds capable of inhibiting the endogenous endothelin producing system or compounds with dual inhibiting activities on NEP and the endogenous endothelin producing system would seem to provide added value in the therapy of cardiovascular diseases like essential hypertension, pulmonary hypertension and/or congestive heart failure. As a result of inhibition of the endogenous endothelin producing system, formation of endothelin would be prevented and thus an increase in peripheral resistance would be counteracted, which consequently leads to a relief of the strain on the heart muscle. As a result of inhibition of the ANP degrading enzyme NEP, higher ANP levels and an increased duration of action of ANP can be achieved. This will lead to a WO 2006/000564 PCT/EP2005/052915 3 reinforcement of the ANP-mediated endogenous cardioprotective mechanism of action. However, because NEP may also be involved in ET degradation, a pure NEP inhibition would, in addition to the desired increase in the ANP levels, also lead to an unfavorable increase in the ET levels. For this reason, a mixed profile with dually acting inhibition of NEP and of the endogenous endothelin producing system is to be regarded as particularly favorable, since it prevents both the breakdown of the natriuretically / diuretically acting ANP (by NEP-blockade), and simultaneously inhibits the formation of ET. As a result, the adverse attendant effect of pure NEP-inhibitors (increase in the endothelin levels) no longer comes to bear. Compounds with a dually acting combined inhibitory effect on NEP and the endogenous endothelin producing system, i.e. benzazepine-, benzoxazepine- and benzothiazepine-N-acetic acid derivatives, are known from document EP 0 733 642 Al. Further favourable pharmacological properties of compounds falling within the structural scope of EP 0 733 642 Al are known from documents EP 0 830 863 Al, WO 00/48601 Al and WO 01/03699 Al. Phosphonic acid substituted benzazepinone-N-acidic acid derivatives with a combined inhibitory effect on NEP and the endogenous endothelin producing system are disclosed in document EP 0 916 679 Al. Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine N-acetic acid derivatives which are useful e.g. for the prophylaxis and/or treatment of cardiovascular conditions or diseases, are disclosed in document WO 2005/030795 Al. From document WO 02/094176 A2 it is known that certain compounds, including those disclosed in document EP 0 733 642 Al and in document EP 0 916 679 Al, may inhibit the endogenous endothelin producing system via an inhibition of metalloprotease IGS5. The metalloprotease IGS5 is also known as human soluble endopeptidase (= hSEP) and is described e.g. in document WO 02/094176 A2. Further, WO 02/094176 A2 discloses the use of compounds with combined NEP/hSEP inhibitory activity for the prophylaxis or treatment of inter alla cardiovascular diseases. It is the object of the present invention to provide a novel combination therapy for cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and/or congestive heart failure, with enhanced efficacy and a favourable safety profile. It has now surprisingly been found that a combination of at least one NEP-inhibitor, at least one inhibitor of the endogenous endothelin producing system and additionally at 4 least one AT 1 receptor antagonist, provides still further enhanced efficacy in cardio vascular diseases like essential hypertension, pulmonary hypertension and/or con gestive heart failure, and a favourable safety profile. The invention therefore relates in a first aspect to pharmaceutical compositions 5 comprising pharmacologically effective quantities of each of: a) at least one neutral endopeptidase (NEP)-inhibitor; b) at least one inhibitor of the endogenous endothelin producing system; and c) at least one AT, receptor antagonist selected from the group consisting of can desartan, eprosartan and losartan and any physiologically compatible salts, sol 10 vates, prodrugs or esters thereof, wherein the at least one neutral endopeptidase (NEP) inhibitor (a) and at least one inhibitor of the endogenous endothelin producing system (b) is a dually acting com pound capable of inhibiting neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP), which dually acting compound is daglutril or physiologically 15 compatible salts thereof. The invention also relates to: * a 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 AT 1 receptor antagonist, for the preparation of a medicament for the prophylaxis or 20 treatment of a cardiovascular disease in a mammal including a human; e a use of daglutril, or physiologically compatible salts thereof, and at least one

AT

1 receptor antagonist selected from the group consisting of candesartan, eprosartan and losartan and any physiologcally compatible salts, solvates, prodrugs and esters thereof, for the preparation of a medicament for the prophylaxis or 25 treatment of a cardiovascular disease in a mammal including a human; * a method for the prophylaxis or treatment of a cardiovascular disease in a mammal including a human, the method comprising administering to the mammal a therapeutically effective amount of at least one neutral endopeptidase inhibitor in combination with at least one inhibitor of the endogenous endothelin producing 30 system and at least one AT 1 receptor antagonist; and * a method for the prophylaxis or treatment of a cardiovascular disease in a mammal including a human, the method comprising administering to the mammal 4a daglutril, or physiologically compatible salts thereof, and at least one AT 1 receptor antagonist selected from the group consisting of candesartan, eprosartan and losartan and any physiologically compatible salts, solvates, prodrugs and esters thereof. 5 The pharmaceutical compositions according to the invention may further and preferably comprise conventional pharmaceutically acceptable auxiliaries and/or car riers. The pharmaceutical compositions according to the invention may further com prise acetylsalicylic acid. Inhibitors of the endogenous endothelin producing system can be selected from 10 the group consisting of inhibitors of ECE, inhibitors of hSEP and dually acting com pounds capable of inhibiting ECE and hSEP. Dually acting compounds capable of inhibiting ECE and hSEP are preferred. In the pharmaceutical compositions according to the invention, the subcombina tion of at least one NEP-inhibitor (a) and at least one inhibitor of the endogenous en 15 dothelin producing system (b) can preferably be realized by a dually acting compound capable of inhibiting NEP and the endogenous endothelin producing system. Pre ferred are dually acting compounds capable of inhibiting NEP and hSEP. Particularly preferred are the dually acting compounds of general Formula 1, H A N o N

COOR

1 20 wherein R' is hydrogen or a group forming a biolabile carboxylic acid ester A represents a group selected from the subgroups a, WO 2006/000564 PCT/EP2005/052915 5 Ra

R

2 00C wherein

R

2 is hydrogen or a a group forming a biolabile carboxylic acid ester and

R

3 is a phenyl-C 1 --alkyl group which can optionally be substituted in the phenyl ring by C 14 -alkyl, C 14 -alkoxy or halogen; or a naphthyl-C 4 -alkyl group; or b,

R

5 0 - ,

R

4 0 wherein

R

4 is hydrogen or a group forming a biolabile phosphonic acid ester and

R

5 is hydrogen or a group forming a biolabile phosphonic acid ester; or c, 0

R

8 R7/ c RSOOC

R

6 00C wherein R6 is is hydrogen or a group forming a biolabile carboxylic acid ester, R7 is hydrogen, C 1 --alkyl or C 1 -- hydroxyakyl, the hydroxyl group of which is optionally esterified with C 24 -alkanoyl or an amino acid residue, and Ra is C 1 -alkyl; ClA-alkoxy-C14-alkyl; C 1 4-hydroxyalkyl, which is optionally substituted by a second hydroxyl group and the hydroxyl groups of which are each optionally esterified with C 2 4-alkanoyl or an amino acid residue; (Co 4 -alkyl) 2 amino-C.e 6 -alkyl; C3-rcycloalkyl; C3-rcycloalkyl-C 1 4-alkyl; phenyl-C 1 -- alkyl, the phenyl group of which is optionally substituted 1-2 times by C 1 4-alkyl, C 1 -- alkoxy and/or halogen; naphthyl-C4-alkyl; Ca oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times by C 1 -alkyl, C 1 -- alkoxy and/or halogen, or 2 oxoazepanyl, or WO 2006/000564 PCT/EP2005/052915 6

R

7 and R 8 together are C 47 -alkylene, the methylene groups of which are optionally replaced 1-2 times by carbonyl, nitrogen, oxygen and/or sulphur and which are optionally substituted once by hydroxy, which is optionally esterified with C 2 w-alkanoyl or an amino acid residue; C-alkyl; C 1 w-hydroxyalkyl, the hydroxyl group of which is optionally esterified with C 24 -alkanoyl or an amino acid residue; phenyl or benzyl, and/or physiologically compatible salts of acids of Formula I and/or physiologically com patible acid addition salts of compounds of Formula Ic. Where the substituents in the compounds of Formula I are or contain C 14 -alkyl groups, these may be straight-chain or branched. Where biolabile ester forming groups in the compounds of Formula I are or contain lower alkyl groups, these may be straight chain or branched and contain usually I to 4 carbon atoms. Where the substituents con tain halogen, fluorine, chlorine or bromine, preferably fluorine or chlorine, are particularly suitable. Where substituents contain C 2 w-alkanoyl, this may be straight-chain or branched. Acetyl is preferred as C2A-alkanoyl. Where substituents are biolabile ester forming groups, these as a rule represent prodrugs of the active drug prinicple. Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites. Prodrugs are bioreversi ble derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeabil ity, stability, presystemic metabolism and targeting limitations (see e.g. Medicinal Chem istry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. 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 investigational 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, pharmacologically neutral organic amines such as, for example, diethylamine or tert.-butylamine.

WO 2006/000564 PCT/EP2005/052915 7 Preferred are the compounds of general Formula Ia,

R

3 H

R

2 00C N Ia o N

COOR

1 wherein R 1 , R 2 and R 3 have the above meanings, and physiologically compatible salts of acids of Formula Ia. Preferred salts of compounds of Formula Ia are e.g. disclosed in document WO 03/059939 Al which is incorporated herein by reference. The compounds of Formula Ia contain two chiral carbon atoms, namely the carbon atom which is in the 3 position of the ring framework (= 3-position) and bears the amide side-chain, and the carbon atom of the amide side-chain which bears the radical R 3 (= 2'-position). The com pounds can therefore exist in several optically active stereoisomeric forms or as a race mate. According to the present invention both the racemic mixtures and the isomerically pure compounds of Formula Ia may be used. The compounds of Formula Ia are optionally esterified dicarboxylic acid derivatives. Depending on the form of administration, biolabile monoesters, particularly compounds in which R 2 is a group forming a biolabile ester and R 1 is hydrogen, or dicarboxylic acids are preferred, the latter being particularly suitable for i.v. administration. Groups which can be cleaved under physiological conditions in vivo, releasing bioavailable derivatives of the compounds of Formula Ia, are suitable as groups forming biolabile carboxylic acid esters R 1 and R 2 . Suitable examples of this are C-alkyl groups, in particular methyl, ethyl, n-propyl and isopropyl; C-alkyloxy-C-alkyloxy-C-alkyl groups, in particular methoxyethoxymethyl; C3-rcycloalkyl groups, in particular cyclohexyl; C3+cycloalkyl-C alkyl groups, in particular cyclopropylmethyl; N,N-di-(Cw-alkyl)amino-C-alky groups; phenyl or phenyl-Cw4-alkyl groups optionally substituted in the phenyl ring once or twice by halogen, C 1 w-alkyl or C-alkoxy or by a C-alkylene chain bonded to two adjacent carbon atoms; dioxolanylmethyl groups optionally substituted in the dioxolane ring by C 1 . 4 -alkyl; C 26 -alkanoyloxy-C-alkyl groups optionally substituted at the oxy-C 4 -alkyl group by C 4 -alkyl; double esters like 1-[[(C-alkyl)carbonyl]oxy]C-alky esters, e.g. (RS)-1 [[(isopropyl)carbonyl]oxy]ethyl or (RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropy (for prepa ration see e.g. F.W. Sum et al., Bioorg. Med. Chem. Lett. 9 (1999) 1921-1926 or Y. Yo shimura et al., The Journal of Antibiotics 39/9 (1986) 1329-1342 ); carbonate esters like 1-[[(C 47 -cycloalkyloxy)carbonyl]oxy] C 14 -alkyl esters, preferably (RS)-1-[[(cyclohexyloxy)- WO 2006/000564 PCT/EP2005/052915 8 carbonyl]oxy]ethyl (= cilexetil; for preparation see e.g. K. Kubo et al., J. Med. Chem. 36 (1993) 2343-2349, cited as "Kubo et al." hereinafter)) or 2-oxo-1,3-dioxolan-4-yl- C 14 alkyl esters which optionally contain a double bond in the dioxolan ring, preferably 5 methyl-2-oxo-1,3-dioxolen-4-yl-methyl (= medoxomil, for preparation see e.g. Kubo et al.) or 2-oxo-1,3-dioxolan-4-yl-methyl (= (methyl)ethylenecarbonate). Where the group form ing a biolabile ester represents an optionally substituted phenyl-C 14 -alkyl group, this may contain an alkylene chain with 1 to 3, preferably 1, carbon atoms and preferably stands for optionally substituted benzyl, in particular for 2-chlorobenzyl or 4-chlorobenzyl. Where the group forming a biolabile ester represents an optionally substituted phenyl group, the phenyl ring of which is substituted by a lower alkylene chain, this may contain 3 to 4, preferably 3, carbon atoms and in particular be indanyl. Where the group forming a bio labile ester represents an optionally substituted C 2 .-alkanoyloxy-C 14 -alkyl group, the

C

2

-

6 -alkanoyl group may be straight-chain or branched.

R

1 preferably has the meanings hydrogen, C 14 -alkyl, p-methoxybenzyl, N,N-di-(CO 4 alkyl)amino-C-alkyl, (RS)-1-[[(isopropyl)carbonyl]oxy]ethyl, (RS)-1-[[(ethyl)carbonyl] oxy]-2-methylpropyl, (RS)-1 -[[(cyclohexyloxy)carbonyloxy]ethyl, 5-methyl-2-oxo-1,3 dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methyl or (RS)-1-[[(ethoxy)carbonyl]oxy] ethyl.

R

2 preferably has the meanings hydrogen, ethyl, methoxyethoxymethyl, (RS)-1 [[(isopropyl)carbon91]oxylethyl, (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-1,3 dioxolan-4-yl-methyl or (RS)-1-[[(ethoxy)carbonyl]oxy]ethyl. More preferred are the compounds which are selected from the group consisting of 2-[1 -(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepin-3-ylcarbamoyl)-cyclo pentylmethyl]-4-phenyl-butyric acid ethyl ester [alternative name: 3-[1-{2'-(ethoxycarbo nyl)}-4'-phenylbutyl]-cyclopentan-l-carbonylamino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-benz azepin-1-acetic acid] of Formula 11, Et00C H ONN a 0 0

\ICOOH

WO 2006/000564 PCT/EP2005/052915 9 2-[1 -(1 -carboxymethyl-2-oxo-2,3,4,5-tetrahydro-I H-benzo[b]azepin-3-ylcarbamoyl)-cyclo pentylmethyl]-4-naphthalen-1-yl-butyric acid ethyl ester [alternative name: 3-[l-{2 (ethoxycarbonyl)-4-(I-naphthyl)butyl]cyclopentyl}carbonyl)amino]-2-oxo-2,3,4,5-tetrahy dro-1 H-1-benzazepin-1-yl}acetic acid] of Formula 111, EtOOC III O N 0 COOH 2-[1 -(1 -carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepin-3-ylcarbamoy)-cyclo pentylmethyl]-4-phenyl-butyric acid of Formula IV, HO O O 0~ O

-

OH 2-[1 -(1 -carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepin-3-ylcarbamoyl)-cyclo pentylmethyl]-4-naphthalen-1-yl-butyric acid of Formula V, HO O O 0 IrOH and physiologically compatible salts of the acids of Formulas II, Ill, IV and/or V. The com pounds of Formulas I1, Ill, IV and V are especially suited in their 3S,2'R forms. Most pre ferred is the compound of Formula II in its 3S,2'R form, also known as "daglutril" or "SLV306". The compounds of Formula la are known, for example, from document EP 0 733 642 Al which is incorporated herein by reference, and can be produced according to WO 2006/000564 PCT/EP2005/052915 10 the production processes disclosed or referenced in this document or analogously to said production processes. Further, compounds of general Formula lb, 0 H RO P N I R50 / PjN lb

R

4 0 0 N COOR' wherein R', R 4 and R6 have the meanings given above, or physiologically compatible salts of acids of Formula lb can be used as dually acting compounds capable of inhibit ing NEP and the endogenous endothelin producing system. The compounds of Formula lb are known, for example, from document EP 0 916 679 Al which is incorporated herein by reference, and can be produced according to the production processes disclosed or referenced in this document or analogously to said production processes. Suitable groups R 1 forming biolabile carboxylic acid esters in compounds of For mula lb are those as specified for compounds of Formula [a above. Groups R 4 and R suitable as groups forming biolabile phosphonic acid esters are those which can be removed under physiological conditions in vivo with release of the respective phosphonic acid function. For example, groups which are suitable for this pur pose are lower alkyl groups, C 2

-C

6 -alkanoyloxymethyl groups optionally substituted on the oxymethyl group by lower alkyl, or phenyl or phenyl-lower alkyl groups whose phenyl ring is optionally mono- or polysubstituted by lower alkyl, lower alkoxy or by a lower al kylene chain bonded to two adjacent carbon atoms. If the group R 4 and/or R 5 forming a biolabile ester is or contains lower alkyl, this can be branched or unbranched and can contain 1 to 4 carbon atoms. If R 4 and/or R are an optionally substituted alkanoyloxy methyl group, it can contain a preferably branched alkanoyloxy group having 2 to 6, preferably 3 to 5, carbon atoms and can, for example, be a pivaloyloxymethyl radical (= tert-butylcarbonyloxymethyl radical). If R 4 and/or R 5 are an optionally substituted phenyl lower alkyl group, this can contain an alkylene chain having 1 to 3, preferably 1, carbon atoms. If the phenyl ring is substituted by a lower alkylene chain, this can contain 3 to 4, in particular 3, carbon atoms and the substituted phenyl ring is in particular indanyl.

WO 2006/000564 PCT/EP2005/052915 11 The compounds of the formula lb contain a chiral carbon atom, namely the carbon atom carrying the amide side chain in the 3-position of the benzazepine structure. The compounds can thus be present in two optically active stereoisomeric forms or as a ra cemate. The present invention includes both the racemic mixtures and the isomerically pure compounds of the formula 1. If R 4 and R in compounds of the formula lb are not hydrogen and in each case have different meanings, the phosphorus atom of the phos phonic acid group can also be chiral. The invention also relates to the isomer mixtures and isomerically pure compounds of the formula lb formed as a result of chiral phospho rus atoms. When compounds of Formula lb are used according to the invention, (3-{[l (benzyloxy-ethoxy-phosphorylmethyl)-cyclopentanecarbonyl]-amino}-2-oxo-2,3,4,5-tetra hydro-benzo[b]azepin-1-y)-acetic acid tert-buty ester and isobutyric acid 1-[[1-(-1 carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepin-3-ylcarbamoyl)-cyclopentyl methyl]-(l-isobutyryloxy-ethoxy)-phosphinoyloxy]-ethyI ester are preferred. Both of said compounds are particularly preferred when the stereochemistry at the chiral carbon atom (see above) is "S", namely in their "(3S)" configuration. The compounds of Formula lb are known, for example, from document EP 0 916 679 Al, and can be produced according to the production processes disclosed or referenced in this document or analogously to said production processes. Also preferred are the compounds of general Formula Ic, 0 N R7H

R

6 00C NI R)OC O N 0

COOR

1 wherein R 1 , R 6 , R 7 and R 8 have the above meanings, and physiologically compatible salts of acids of Formula Ic and/or physiologically compatible acid addition salts of com pounds of Formula Ic, for the use as dually acting compounds capable of inhibiting NEP and the endogenous endothelin producing system in pharmacological compositions ac cording to the invention. The compounds of Formula Ic are known, for example, from document WO 2005/030795 Al which is incorporated herein by reference, and can be produced according to the production processes disclosed or referenced in this docu ment or analogously to said production processes.

WO 2006/000564 PCT/EP2005/052915 12 Where in compounds of Formula Ic the substituents R and/or R" contain basic groups, in particular nitrogen, the compounds of Formula Ic may also occur in the form of acid addition salts.Physiologically compatible acid addition salts of compounds of For mula Ic are their conventional salts with inorganic acids, for example sulphuric acid, phosphoric acid or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example lower aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, or with sulphonic acids, for example lower alkanesulphonic acids such as methanesulphonic acid. Suitable groups R' forming biolabile carboxylic acid esters in compounds of For mula Ic are those as specified for compounds of Formula [a above. Suitable groups R 6 forming biolabile carboxylic acid esters in compounds of Formula Ic are the same as specified for groups R 2 in compounds of Formula la above.

R

7 preferably has the meanings hydrogen, methyl, ethyl, 2-hydroxyethyl or 3 hydroxypropyl, each hydroxyl group optionally being esterified with C2-alkanoyl or an amino acid residue. Where R 8 has the meaning (Co"-alkyl) 2 amino-C1.e-alkyl, one or two Co"-alkyl groups can independently of each other be present. More specifically, "(Co4-alkyl) 2 amino-C 1

.

6 alkyl" expressly comprises the meanings "(Co) 2 -alkylamino-C 1

.

6 -alkyf", "(Co)(C4)-alkyl amino-C 1 .e-alkyl" and "(Ci-) 2 -alkylamino-C..eglikyl". "(Co) 2 -alkylamino-C 1

..

6 -alkyl" is meant to denominate an unsubstituted primary (= -NH 2 ) amino group bonded to C 1

.

6 -alkyl(en); "(Co)(C4)-alkylamino-C 1 .-- alkyl" is meant to denominate a secondary amino group mono substituted by (C 1 -)-alkyl and bonded to C 1 ..-alkyl(en); "(C4) 2 -alkylamino-C1.

6 -alkyl" is meant to denominate a tertiary amino group disubstituted by (C4)-alkyl and bonded to

C

1 .- alkyl(en). R preferably has the meanings isopropyl; methoxyethyl; 2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group optionally being esterified with C 2 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 1,1-dimethylbutyl; phenyl-2-oxoethyl; 2-(4-methoxyphenyl)-2-oxoethyl; 3-(2-oxoaze panyl); (Co--alkyl) 2 amino-C 1 .e-alkyl, in particular dimethylamino-n-propyl, (methyl)amino ethyl, amino-n-propyl, amino-n-butyl or amino-n-pentyl. Where R and R3 together are C4-ralkylene, the methylene groups of which are op tionally replaced or optionally substituted, in each case morpholine; piperidine; 4 ketopiperidine; 4-hydroxypiperidine, optionally being esterified with C 2 4-alkanoyl or an amino acid residue at the hydroxyl group; piperazine or pyrrolidine is preferred.

WO 2006/000564 PCT/EP2005/052915 13 Where in the compounds of Formula Ic hydroxyl groups are esterified with amino acid residues, these amino acid residues may be derived from natural or non-natural, aX or P-amino acids. Suitable amino acids which can be used are for example selected from the group cosisting of alanine, 2-aminohexanoic acid (= norleucine), 2-aminopentanoic acid (= norvaline), arginine, asparagine, aspartic acid, cysteine, 3,4-dihydroxy phenylalanine (= 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, tryptophan, tyrosine and valine. Preferred are amino acid residues which are derived from alanine, asparagine, glutamine, glycine, isoleucine, leucine, lysine, ornithine, phenylalanine, proline and valine. The compounds of Formula Ic contain two chiral carbon atoms, namely the carbon atom bearing the amide side chain in position 3 of the benzazepine skeleton (= Cb*) and the carbon atom bearing the radical "-COOR 6 " (= C.*). The compounds can thus be pre sent in a total of four stereoisomeric forms. The present invention comprises both the mixtures of stereoisomers and enantiomers, and also the isomerically pure compounds of Formula Ic. Isomerically pure compounds of Formula Ic are preferred. Particularly pre ferred are compounds of Formula Ic wherein the carbon atom bearing the amide side chain in position 3 of the benzazepine skeleton is in the "S" configuration. With respect to the chiral carbon atom "*Ca" bearing the radical '-COOR 6 ", the configuration of the compounds of Formula I which is preferred according to the invention in the context of this invention is provisionally assigned the configuration designation "rell". It can be de rived by analogous observations of suitable compounds of known configuration that the preferred configuration relic " at the chiral centre "*Ca" is probably likewise the "S" con figuration. Particularly preferred compounds of Formula Ic are selected from the group con sisting of 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yI]amino} carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxobutanoic acid; 2-{[1-({{1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3 yl]amino}carbonyl)cyclopentyl]methyl}-4-(dimethylamino)-4-oxobutanoic acid; 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3 yl]amino}carbonyl)cyclopentyl]methyl}-4-(diethylamino)-4-oxobutanoic acid; WO 2006/000564 PCT/EP2005/052915 14 2-{[1 -({[1 -(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 H-1 -benzazepin-3-yl]amino}car bonyl)cyclopentyl]methyl}-4-[(2-hydroxyethyl)(methyl)amino]-4-oxobutanoic acid; 2-{{I-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-I H-1-benzazepin-3-yl]amino}car bonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)(methyl)amino]-4-oxobutanoic acid; 2-{[1-({[l -(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepin-3-yl]amino} carbonyl)cyclopentyl]methyl}-4-(4-hydroxypiperidin-1-yI)-4-oxobutanoic acid; 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino} carbonyl)cyclopentyl]methyl}-4-oxo-4-[4-(L-valyloxy)piperidin-1-yI]butanoic acid; 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino} carbonyl)cyclopentyl]methyl}-4-morpholin-4-yI-4-oxobutanoic acid; 2-{[I-({[I-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-IH-1-benzazepin-3-y]amino} carbonyl)cyclopentyl]methyl}-4-oxo-4-(4-oxopiperidin-1-yl)butanoic acid; 4-[bis(2-hydroxyethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1 benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic acid; 2-{[1-({[I-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}car bonyi)cyclopenty]methyl}-4-{ethyl[3-(ethylamino)propyl]amino)-4-oxobutanoic acid; 2-{[1-({[I-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-IH-1-benzazepin-3-yljamino} carbonyl)cyclopentyl]methyl}-4-[[2-(dimethylamino)ethyl](methyl)amino]-4-oxobutanoic acid; 4-[(3-aminopropyl)(ethy)amino]-2-{[ -({[ -(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 H-1 benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic acid, 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-y]amino} carbonyl)cyclopentyl]methyl}-4-{methyl[2-(methylamino)ethyl]amino)-4-oxobutanoic acid; 4-[(4-aminobutyl)(methyl)amino]-2-{[I-({(1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H 1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic acid; 4-[(4-aminobutyl)(ethyl)amino]-2-{[1-({[I-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1 benzazepin-3-yl]aminocarbonyl)cyclopentyl]methyl}-4-oxobutanoic acid; 2-{{I-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yI]amino} carbonyl)cyclopentyl]methyl}-4-{methyl[3-(methylamino)propyl]amino}-4-oxobutanoic acid and WO 2006/000564 PCT/EP2005/052915 15 4-[(5-aminopentyl)(methyl)amino]-2-{[1 -({[1 -(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 H 1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic acid, together with their biolabile esters and physiologically compatible salts of acids of these compounds of Formula Ic and/or physiologically compatible acid addition salts of these compounds of Formula Ic.

AT

1 receptor antagonists are pharmacologically active drug compounds which are capable to selectively block the AT 1 subtype of the angiotensin I receptor in mammals and humans and which are known to possess e.g. antihypertensive properties. AT 1 re ceptor antagonists which can be used according to the present invention may be se lected from the group consisting of abitesartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesar tan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B1/081, 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-1 1194, DA-2079, DE-3489, DMP-81 1, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-771 1, 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 physiologically compatible salts, solvates, prod rugs or esters thereof. Preferred AT 1 receptor antagonists are selected from the group consisting of abite sartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, losartan, milfasartan, olmesartan, opo misartan, pratosartan, ripisartan, saprisartan, tasosartan, telmisartan, valsartan, zolasar tan; Kissei KRH-94, Lusofarmaco LR-B/081, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247 or any physiologically compatible salts, solvates, prodrugs or esters thereof. Candesartan, eprosartan and losartan are more preferred AT, receptor antagonists. Eprosartan is usually used in the form of its mesylate. Losartan is usually WO 2006/000564 PCT/EP2005/052915 16 used in the form of losartan potassium. Candesartan is usually used in the form of can desartan cilexetil. Further pharmaceutical compositions which can be favourably used in the treat ment and/or prophylaxis of cardiovascular conditions or diseases comprise pharmaco logically effective quantities of each of a) at least one NEP-inhibitor as a first active agent, b) at least one inhibitor of the endogenous endothelin producing system as a second active agent and d) at least one classic cardiovascular drug as a third or further active agent. Suitable classic cardiovascular drugs can be selected from the group consisting of non-selective alpha-adrenoceptor antagonists, e.g. tolazoline or phenoxybenzamine; selective alpha-adrenoceptor antagonists, e.g. doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, e.g. acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; mixed antagonists of alpha- and beta-adrenoceptors, e.g. carvedilol or labetolol; ganglion blockers, e.g. reser pine or guanethidine; alpha2-adrenoceptor agonists (including centrally acting alpha2 adrenoceptor agonists), e.g. clonidine, guanfacine, guanabenz methyldopa and moxonidine; renin-inhbifths, e.g. alskiren; ACE-inhbitors, e.g. benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; mixed or selective endothelin receptor antagonists e.g. atrasen tan, bosentan, clazosentan, darusentan, sitaxsentan, tezosentan, BMS-193884 or J 104132; direct vasodilators, e.g. diazoxide, dihydralazine, hydralazine or minoxidil; mixed ACE/NEP-inhbitors, e.g. omapatrilat; ECE-inhbitors, e.g. 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 il receptor antagonists. Preferably, the classic cardiovascular drugs may be administered together with a drug selected from the group consisting of 2-[1-(1-Carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin 3 -ylcarbamoyl)-cyclopentylmethyl]-4-pheny-butyric acid ethyl ester; 2-[1-(1 Carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo~b]azepin-3-ylcarbamoyl)-cyclo pentylmethylj-4-naphthalen-1-yl-butyric acid ethyl ester; 2-[1-(1-Carboxymethyl-2-oxo 2,3,4,5-tetrahydro-1 H-benzo[b]azepin-3-ylcarbamoyl)-cyclopentylmethyl]-4-phenyl-butyric acid; 2-[1-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)- WO 2006/000564 PCT/EP2005/052915 17 cyclopentylmethyl]-4-naphthalen-1-yl-butyric acid; and their physiologically compatible salts. More preferred, the classic cardiovascular drugs may be administered together with daglutril. The pharmaceutical compositions according to the invention can be prepared in a manner known per se and thus can be obtained as formulations suitable for enteral, such as oral or rectal, or parenteral administration to mammals or humans, comprising a thera peutical effective amount of the pharmacologically active agents, alone or in combination with one or more pharmaceutically acceptable auxiliaries and/or carriers, especially suit able for enteral or parenteral application. Pharmaceutical compositions for enteral or par enteral administration are, for example, in unit dosage forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Typical oral formulations include coated tablets, tablets, capsules, syrups, elixirs and suspensions. Capsules may contain the active agents e.g. in form of powders, granules, pellets, beadlets or microtablets. For example, a pharmaceutical composition according to the invention may consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active agents, the rest being made up by pharmaceutically acceptable auxiliaries and/or carriers. Thus, phar maceutical compositions for oral use can be obtained by combining the active com pounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances. Typical injectable formula tions 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, e.g. in one combined unit dosage form like in one tablet or capsule, i.e. in a physical combination. In such a combined unit dosage form, the different active agents (a), (b) and (c) can be segregated from each other, e.g. by means of different layers in said tablet, e.g. by the use of inert intermediate layers known in the art; or by means of different compartments in said capsule (viz. compartmentalized). The corresponding active agents or their phar maceutically acceptable salts may also be used in form of their hydrates or include other solvents used for crystallization. A unit dosage form may 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 WO 2006/000564 PCT/EP2005/052915 18 eprosartan, daglutril and candesartan or daglutril and losartan are preferred embodi ments of the invention. In another embodiment the active agents (a), (b) and (c) can be obtained and ad ministered in two or more separate unit dosage forms, e.g. in two or more tablets or cap sules, the tablets or capsules being physically segregated from each other. The two or more separate unit dosage forms can be administered simultaneously or stepwise (sepa rately), e.g. sequentially one after the other in either order. Thus, the active agents can be administered in either order at the same time or at different times spread over the day, the optimal dosage regimen usually being determined by prescription of a physician. When a dually acting compound capable of inhibiting NEP and the endogenous endo thelin producing system is used to embody the combination of active agents (a) and (b), the active agents [(a) + (b)] and (c) in the pharmaceutical composition can favourably be present in two separate dosage forms, usually complementary or balanced for combined use, e.g. as two different tablets or capsules, usually further comprising pharmaceutically acceptable auxiliaries and/or carriers, or in different compartments of one single capsule. Thus, in this embodiment at least the AT 1 receptor antagonist is present in a unit single dosage form physically segregated from the other active agent(s). The typical pharmaceutically acceptable auxiliaries and/or carriers for use in the for mulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sul fate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegeta ble oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alco hols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrants, agents, e.g. talcum; buffers, preservatives, antioxidants, lubricants, flavor ing and the like commonly used in pharmaceutical formulations. In a specific embodiment of said first aspect, the invention also relates to a kit com prising in separate containers in a single package pharmaceutical dosage forms for use in combination, comprising, i1) in one separate container a pharmaceutical dosage form comprising at least one neutral endopeptidase inhibitor and in a second separate container a pharmaceuti- WO 2006/000564 PCT/EP2005/052915 19 cal dosage form comprising at least one inhibitor of the endogenous endothelin producing system, or 12) in one separate container a pharmaceutical dosage form comprising a dually acting compound capable of inhibiting neutral endopeptidase and the endogenous endo thelin producing system, and ii) in another separate container a pharmaceutical dosage form comprising at least one AT 1 receptor antagonist. The kit form is particularly advantageous but not limited to the case when the sepa rate components must be administered in different dosage forms or are administered at different dosage intervals. The dosage forms may favourably be oral formulations like tablets or capsules. The separate containers may e.g. be blister packs - in particular where the oral formulations are tablets or coated tablets, boxes or other containers com monly used to package pharmaceutical dosage forms. Preferred are alternatives of the kit which comprise in one separate container a pharmaceutical dosage form comprising a dually acting compound capable of inhibiting neutral endopeptidase and the endogenous endothelin producing system, and in another separate container a pharmaceutical dos age form comprising at least one AT 1 receptor antagonist. The kit may further comprise leaflets or other written instructions as to how the different kit constituents may best be used in order to achieve best therapeutic results with the provided 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 AT 1 receptor antagonist, for the preparation of a pharmaceutical com position or medicament for the prophylaxis or treatment of a cardiovascular disease, in particular hypertension and/or cardiac insufficiency; essential hypertension and/or pul monary hypertension in mammals and humans. In a third aspect, the invention relates to a method of treating or preventing a car diovascular disease in mammals and humans comprising administering to a subject in need thereof 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 AT 1 re ceptor antagonist. Subjects in need of such treatments are in particular those humans or mammals who are suffering from or being susceptible to a cardiovascular disease, in particular hypertension and/or cardiac insufficiency; essential hypertension and/or pul monary hypertension. Further, the combination treatment according to the present inven- WO 2006/000564 PCT/EP2005/052915 20 tion is also deemed suitable or beneficial for the treatment and/or prevention of endothe lial dysfunction and/or sexual dysfunction, in particular male dysfunction, more particular erectile dysfunction. The active agents (a), (b) and (c) can be obtained and administered together, sequentially one after the other or separately in one combined unit dosage form, e.g. in one tablet or capsule. Thus, the active agents can be administered in either order at the same time or at different times spread over the day, the optimal dosage regimen usually being determined by prescription of a physician. In one specific embodiment of said third aspect, a fixed combination of a dually acting compound capable of inhibiting neutral endopeptidase and the endogenous endo thelin producing system, and an AT 1 receptor antagonist can be used. Fixed combina tions comprising daglutril and eprosartan, daglutril and candesartan or daglutril and losar tan are preferred alternatives of this specific embodiment. Description of the pharmacological test methods The beneficial effects of the combination therapy according to the invention can e.g. be shown in a clinical test protocol and in an animal model at the rat: Clinical test protocol A randomized, placebo-controlled, parallel group, multi-center, single dose study of oral daglutril (vide supra) during 12-hour right heart catheterization in human subjects with congestive heart failure (= CHF) was performed. Each subject received one dose of daglutril or placebo. The study consisted of three visits (or study days when in-subjects were included). Ambulatory subjects were in hospital for two nights and one day. Criteria for evaluating efficacy were systemic vascular resistance (= SVR), pulmo nary capillary wedge pressure (= PCWP), cardiac output (= CO), heart rate (= HR), pul monary and systemic systolic, diastolic and mean pressures; pulmonary vascular resi stance (= PVR); stroke volume index (= SVI); cardiac index (= Cl); transpulmonary gra dient and neurohormones. The primary efficacy parameter was the maximum decrease from baseline over 6 hours for SVR and was compared between treatment groups using analysis of covari ance, with the baseline value as covariate and center and NYHA classification as factors. Testing was carried out one-sided at an overall significance level of a=0.05. Adjustment for the multiple comparisons artifact was controlled by applying Dunnett's procedure. In addition, the existence of a dose-response relationship for daglutril was evaluated by WO 2006/000564 PCT/EP2005/052915 21 investigating linear, quadratic and cubic contrasts. The secondary efficacy parameter was the maximum change from baseline for PCWP and was analyzed in the same way as the primary variable. The maximum decrease from baseline over 12 hours, the change from for each individual time point and the adjusted area under the curve (= AUC) over 6 and 12 hours were analyzed for SVR and PCWP, using similar statistical methodology as for the main parameter of interest. All other tertiary efficacy parameters were analyzed using the same statistical methodology as for the primary efficacy para meter. Criteria for evaluating safety were laboratory variables; electrocardiogram (= ECG); physical examinations; vital signs and adverse events (= AEs). Criteria for inclusion comprised male or female (without childbearing potential) sub jects, aged > 18 to 5 85 years, with a history of chronic, symptomatic, mild to severe (NYHA Class ll-IV) CHF for at least three months, with documented systolic dysfunction (left ventricular ejection fraction (= LVEF) 35% by echocardiography) receiving a stable dose of their individually optimized medication regimen for at least one week prior to study enrollment. (96) Subjects were screened and (75) were randomized and analyzed, (18) sub jects in the 200 mg daglutril group, (20) subjects in the 400 mg daglutril group, (19) sub ejects in the 800 mg daglutril group and (18) subjects in the plac.bo group. In a subgroup analysis, the 75 randomized subjects in the study were divided into subgroups, namely placebo or daglutril treatment with criterion present or absent. As criterion was taken whether concomitant medication of losartan potassium was taken prior to and continued after randomization. In the placebo group I patient took losartan potassium whereas 15 patients did not take losartan potassium. In the daglutril group 5 patients took losartan potassium whereas 49 patients did not take losartan potassium. Summary statistics of the average over the first 6 hours (0.5, 6 hours; only com puted if no time points have missing data) (mean, Standard Deviation (= SD), n) are given. Both, for the criterion present and absent subgroups, the placebo corrected mean values and summary statistics (mean change, standard error of change (= SE) and stan dardized mean change (= mean/SE) are given. In this test model, administration of daglutril in addition to a concomitant medication with an AT 1 receptor antagonist (losartan) prior to and after randomisation, respectively, WO 2006/000564 PCT/EP2005/052915 22 showed the results on placebo corrected mean change of mean pulmonary artery pres sure (= MPAP; 0.5-6hrs) as given in table I below: Table 1: Pharmacological results of coadministration of daglutril and ATe-receptor an tagonist (losartan potassium) on MPAP daglutril and no AT-receptor daglutril with ATr-receptor antagonist [mm Hg] (SE) antagonist [mm Hg] (SE) Placebo corrected mean change of MPAP -3.35 (1.06) - 7.44 (3.45) (average 0.5-6 hrs) The test results show that the beneficial influence on pulmonary blood pressure of a dually acting compound capable of inhibiting NEP and the endogenous endothelin pro ducing system, namely daglutril, in addition to an ATrreceptor antagonist was relevantly more marked than the influence that resulted from administration of a dually acting com pound of inhibiting NEP and the endogenous endothelin producing system, namely daglutril, alone. Animal test model Male spontaneously hypertensive rats (= SHR, insulin resistant strain from Charles River; aged 6 months) were equipped with telemetry transmitters for continuous monitor ing of blood pressure and heart gte (as described below). After 3 days of monitoring under baseline (untreated) conditions, animals were divided into two groups receiving an AT,-receptor antagonist (eprosartan mesylate, hereinafter referred to as experiment I; or candesartan cilexetil, hereinafter referred to as experiment I) or an AT,-receptor antago nist plus daglutril in combination. In experiment Il, a third group of rats was included, re ceiving only daglutril. Compounds were administered via the drinking water, and daily drug intake was measured by weighing the water bottles thrice weekly. Intended daily doses in experiment I were 60 mg/kg/day of eprosartan mesylate plus, in the combina tion group, 100 mg/kg/day of daglutril. In experiment i, intended daily doses were I mg/kg of candesartan cilexetil, and 100 mg/kg of daglutril in the daglutril only and the combination group. Telemetry transmitters for continuous monitoring of blood pressure, heart rate and locomotor activity (TA11PA-C40, Data Sciences, USA) were implanted intraabdominally under inhalative halothane anesthesia. A midline abdominal incision was made, and the abdominal aorta was visualized by removal of retroperitoneal fat and connective tissue. A ligature was placed caudal of the renal arteries, the aorta was punc tured with a 22G needle, and the catheter was advanced into the aorta. The entry point was sealed with tissue adhesive (Vetbond*, 3M, USA), the ligature was removed, and WO 2006/000564 PCT/EP2005/052915 23 the abdominal incision was closed. Measurements of aortic pressure were taken every 5 minutes (= min) for 4 seconds (= s) each at a sampling rate of 500 Hz, and were cor rected for the corresponding ambient pressure (ambient pressure monitor, CI PR, Data Sciences, USA). Concentrations of ATyreceptor antagonists and daglutril in the drinking water were adjusted once per week, in order to ensure the intended daily intake. In experiment I, the average daily water intake throughout the 33 days treatment period amounted to 51 and 56 mI/kg in the eprosartan and eprosartan plus daglutril group, respectively, resulting in the uptake 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 water intake during the 25 days treatment period was 64 ml/kg (candesartan only), 62 ml/kg (daglutril only) and 62 ml/kg (candesartan plus daglutril), resulting in daily doses of 0.9 mg/kg of candesartan in both, the candesartan and combination group, and 101 mg/kg and 98 mg/kg of daglutril in the daglutril and combination group, respectively. The blood pressure, heart rate and activity values, sampled in 5 min intervals by the Dataquest system, were used for calculation of individual 24 hours (= h) -means. These 24 h means were exported to Excel, and group mean values of systolic blood pressure (= SBP), diastolic blood pressure (= DBP), heart rate (= HR), and locomotor activity (= ACT) were calculated for the different treatment groups. For the statistical analysis, a baselini'value (pre) was calculated from 3 days prior to compound ap plication, and ef fects of ATrreceptor antagonist, daglutril and their combination were calculated in rela tion to this baseline value (average value during the treatment period minus baseline value). The statistical comparison was done by using analysis of variance, followed by two-tailed Student's t-test for comparison of AT 1 receptor antagonist and combination groups, both at an error level of P<0.05. In this test model, administration of daglutril, alone and in combination with an AT 1 receptor antagonist (eprosartan mesylate or candesartan cilexetil), and compared to AT, receptor antagonist only administration, showed the results as given in tables 2 and 3 below: WO 2006/000564 PCT/EP2005/052915 24 Table 2: Effects of coadministration of daglutril and ATrreceptor antagonist (eprosar tan mesylate) on cardiovascular parameters in the spontaneously hyperten sive rat daglutril (1) eprosartan eprosartan + Statistics CV Parame- daglutril ters Mean SEM Mean SEM Mean SEM ANOVA DBP [mmHg] 0.8 0.3 -5.6 1.4 -8.3 1.7 P<0.001 SBP [mmHg] -1.5 0.5 -5.9 1.3 -11.7* 1.8 P<0.001 HR [1/min] -2.0 1.6 -7.6 1.7 0.5 * 1.2 P<0.05 Shown are changes vs. matched baseline values measured before the start of treatment; n=5 animals per group; SEM = Standard Error of Measurement, two-tailed ANOVA, n.s. = not significant, * P<0.05 two-tailed t-test eprosartan versus eprosartan + daglutril, (1) data from experiment I Table 3: Effects of coadministration of daglutril and ATi-receptor antagonist (cande sartan cilexetil) on cardiovascular parameters in the spontaneously hyperten sive rat daglutril candesartan tandesartan + Statistics CV Parame- daglutril ters Mean SEM Mean SEM Mean SEM ANOVA DBP [mmHg] 0.8 0.3 -19.7 2.3 -19.9 1.2 P<0.001 SBP [mmHg] -1.5 0.5 -22.8 0.7 -28.9 * 1.7 P<0.001 HR [1/min] -2.0 1.6 -3.0 1.7 -0.2 3.8 n.s. Shown are changes vs. matched baseline values measured before the start of treatment; n=5 animals per group; two-tailed ANOVA, n.s. = not significant, * P<0.01 two-tailed t test candesartan versus candesartan + daglutril 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 receiving the respec tive ATrreceptor antagonist alone. Moreover, daglutril, when given alone, did not lead to a reduction in blood pressure in this model.

26 Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Claims (15)

1. A synergistic pharmaceutical composition comprising pharmacologically effective quantities of each of: a) at least one neutral endopeptidase (NEP)-inhibitor; 5 b) at least one inhibitor of the endogenous endothelin producing system; and c) at least one AT 1 receptor antagonist selected from the group consisting of can desartan, eprosartan and losartan and any physiologically compatible salts, sol vates, prodrugs or esters thereof, wherein the at least one neutral endopeptidase (NEP) inhibitor (a) and at least one 10 inhibitor of the endogenous endothelin producing system (b) is a dually acting compound capable of inhibiting neutral endopeptidase (NEP) and human solu ble endopeptidase (hSEP), which dually acting compound is daglutril or physio logically compatible salts thereof.

2. Pharmaceutical composition according to claim 1, further comprising at 15 least one pharmaceutically acceptable auxiliary or carrier.

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

4. Pharmaceutical composition according to claim 1, wherein said composition comprises an orally administrable dosage form selected from the group consisting of 20 tablets, coated tablets, capsules, syrups, elixirs and suspensions.

5. Pharmaceutical composition according to claim 1 in a unit combined single dosage form, wherein the at least one AT 1 receptor antagonist is physically segregated from the NEP-inhibitor and the inhibitor of the endogenous endothelin producing system. 25

6. Pharmaceutical composition substantially as hereinbefore described with reference to Example 1.

7. A 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 AT, receptor antagonist, for the preparation of a medicament for the prophylaxis or 30 treatment of a cardiovascular disease in a mammal. 28

8. A use of daglutril, or physiologically compatible salts thereof, and at least one AT 1 receptor antagonist selected from the group consisting of candesartan, eprosartan and losartan and any physiologcally compatible salts, solvates, prodrugs and esters thereof, for the preparation of a medicament for the prophylaxis or 5 treatment of a cardiovascular disease in a mammal.

9. Use according to claim 7 or claim 8, wherein the cardiovascular disease is selected from the group consisting of essential hypertension, pulmonary hypertension and congestive heart failure.

10. Use according to any one of claims 7 to 9, wherein the mammal is human, 10

11. A method for the prophylaxis or treatment of a cardiovascular disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one neutral endopeptidase inhibitor in combination with at least one inhibitor of the endogenous endothelin producing system and at least one AT 1 receptor antagonist. 15

12. A method for the prophylaxis or treatment of a cardiovascular disease in a mammal, the method comprising administering to the mammal daglutril, or physiologically compatible salts thereof, and at least one AT 1 receptor antagonist selected from the group consisting of candesartan, eprosartan and losartan and any physiologcally compatible salts, solvates, prodrugs and esters thereof. 20

13. Method according to claim 11 or claim 12, wherein the cardiovascular disease is selected from the group consisting of essential hypertension, pulmonary hypertension and congestive heart failure.

14. Method according to any one of claims 11 to 13, wherein the mammal is human. 25

15. A kit comprising in separate containers in a single package pharmaceutical dosage forms for use in combination, comprising; i) in one separate container a pharmaceutical dosage form comprising a dually acting compound capable of inhibiting neutral endopeptidase and the endoge nous endothelin producing system, which dually acting compound is daglutril or 30 physiologically compatible salts thereof, and 29 ii) in another separate container a pharmaceutical dosage form comprising at least one AT 1 receptor antagonist selected from the group consisting of candesartan, eprosartan and losartan and any physiologically compatible salts, solvates, prodrugs or esters thereof, 5 wherein the kit is so configured to ensure mixing of the contents of the two separate components on use. SOLVAY PHARMACEUTICALS GMBH WATERMARK PATENT & TRADE MARK ATTORNEYS 10 P28221AU00