Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• compositions Comprising NEP-lnhibitors, Inhibitors of the Endogenous Endothelin Producing System and AT 1 Receptor Antagonists
• NEP neutral endopepti- dase
• 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.
• ACE angiotensin converting enzyme
• Document WO 03/059345 A1 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.
• 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.
• 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.
• ANP atrial natriuretic peptide
• 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.
• 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 A1.
• compositions according to the invention may further and pref ⁇ erably comprise conventional pharmaceutically acceptable auxiliaries and/or carriers.
• the pharmaceutical compositions according to the invention may further comprise ace- tylsalicylic acid.
• Inhibitors of the endogenous endothelin producing system can be selected from the group consisting of inhibitors of ECE, inhibitors of hSEP and dually acting compounds capable of inhibiting ECE and hSEP. Dually acting compounds capable of inhibiting ECE and hSEP are preferred.
• the subcombination of at least one NEP-inhibitor (a) and at least one inhibitor of the endogenous endothelin producing system (b) can preferably be realized by a dually acting compound capable of inhibiting NEP and the endogenous endothelin producing system.
• a dually acting compound capable of inhibiting NEP and hSEP are particularly preferred.
• R 1 is hydrogen or a group forming a biolabile carboxylic acid ester
• A represents a group selected from the subgroups a, R 3
• R 2 is hydrogen or a a group forming a biolabile carboxylic acid ester
• R 3 is a phenyl-Ci- 4 -alkyl group which can optionally be substituted in the phenyl ring by Ci- 4 -alkyl, C 1-4 -alkoxy or halogen; or a naphthyl-Ci_ 4 -alkyl group; or
• R 4 is hydrogen or a group forming a biolabile phosphonic acid ester
• R 5 is hydrogen or a group forming a biolabile phosphonic acid ester
• R .6 1 is is hydrogen or a group forming a biolabile carboxylic acid ester
• R 7 is hydrogen, d- 4 -alkyl or the hydroxyl group of which is optionally esterified with C 2- 4-alkanoyl or an amino acid residue, and
• R 8 is Ci- 4 -alkyl; 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; (C tM -alkyOaamino-Ci-e-alkyl; Cs-r-cycloalkyl; Cjj. T -cycloalkyl-Ci.
• substituents in the compounds of Formula I are or contain 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 1 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 2-4 -alkanoyl, this may be straight-chain or branched. Acetyl is preferred as C 2 - 4 -alkanoy
• 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, U(Z), 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. Preferred are the compounds of general Formula Ia,
• 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 A1 which is incorporated herein by reference.
• 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.
• 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 groups, in particular methyl, ethyl, n-propyl and isopropyl; Ci ⁇ -alkyloxy-C ⁇ -alkyloxy-C ⁇ -alkyl groups, in particular methoxyethoxymethyl; Cs ⁇ -cycloalkyl groups, in particular cyclohexyl; C 3-Z- CyClOaI kyl-Ci_ 4 - alkyl groups, in particular cyclopropylmethyl; N.N-di- ⁇ o ⁇ -alkyQamino-Ci-e-alkyl groups; phenyl or phenyl-C 1-4 -alkyl groups optionally substituted in the phenyl ring once or twice by halogen, Cu-alkyl or or by a Ci- 4 -alkylene chain bonded to two adjacent carbon atoms; dioxolanylmethyl groups optionally substituted in the dioxolane ring by Ci- 4 -alkyl; groups optionally substitute
• a biolabile ester represents an optionally substituted phenyI-d- 4 -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.
• 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.
• the group forming a bio ⁇ labile ester represents an optionally substituted C 2-6 -alkanoyloxy-Ci -4 ⁇ alkyl group
• the C 2 - 6 -alkanoyl group may be straight-chain or branched.
• R 1 preferably has the meanings hydrogen, C ⁇ -alkyl, p-methoxybenzyl, N,N-di-(C&4- alkyOamino-Ci-e-alkyl, (RS)-I -[[(isopropyl)carbonyl]oxy]ethyl, (RS)-I -I[(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)-I ⁇ [[(ethoxy)carbonyl]oxy]- ethyl.
• R 2 preferably has the meanings hydrogen, ethyl, methoxyethoxymethyl, (RS)-I- [[(isopropyl)carbon ⁇ I]oxy]ethyl, (RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl, (RS)-I- [[(cyclohexyloxy)carbonyl]oxy]ethyl, 5-methyl-2-oxo-1 ,3-dioxolen-4-yl-methyl, 2-oxo-1 ,3- dioxolan-4-yl-methyl or (RS)-I -[[(ethoxy)carbonyl]oxy]ethyl.
• R 1 , R 4 and R 5 have the meanings given above, or physiologically compatible salts of acids of Formula Ib can be used as dually acting compounds capable of inhibit ⁇ ing NEP and the endogenous endothelin producing system.
• the compounds of Formula Ib are known, for example, from document EP 0 916 679 A1 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 Ib are those as specified for compounds of Formula Ia above.
• Groups R 4 and R 5 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.
• 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 ⁇ ky Ie ne chain bonded to two adjacent carbon atoms.
• 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.
• the compounds of the formula Ib 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 I.
• 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 Ib formed as a result of chiral phospho ⁇ rus atoms.
• 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 Ib are known, for example, from document EP 0 916 679 A1, and can be produced according to the production processes disclosed or referenced in this document or analogously to said production processes.
• 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 A1 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.
• 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.
• inorganic acids for example sulphuric acid, phosphoric acid or hydrohalic acids, preferably hydrochloric acid
• 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 1 forming biolabile carboxylic acid esters in compounds of For ⁇ mula Ic are those as specified for compounds of Formula Ia 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 Ia above.
• R 7 preferably has the meanings hydrogen, methyl, ethyl, 2-hydroxyethyl or 3- hydroxypropyl, each hydroxyl group optionally being esterified with C ⁇ -alkanoyl or an amino acid residue.
• R 8 has the meaning (Co- 4 -alkyl) 2 amino-Ci -6 -alkyl
• one or two Co- 4 -alkyl groups can independently of each other be present.
• alkyl expressly comprises the meanings "(Co) 2 -alkylamino-Ci -6 -alkyr, amino-d-e-alkyl” and "(Ci. 4 )2-alkylamino-C 1- 6 7 .aJkyr.
• (Co)(Ci- 4 )-alkylamino-Ci- 6 -alkyr is meant to denominate a secondary amino group mono- substituted by (Ci. 4 )-alkyl and bonded to Ci -6 -alkyl(en); is meant to denominate a tertiary amino group disubstituted by (C 1-4 )-alkyl and bonded to Ci- 6 -alkyl(en).
• R 8 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); (C ⁇ M -alkyl) 2 amino-Ci -6 -alkyl > in particular dimethylamino-n-propyl, (methyl)amino- ethyl, amino-n-propyl, amino-n
• R 7 and R 8 together are C ⁇ r-alkylene, 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.
• hydroxyl groups are esterified with amino acid residues, these amino acid residues may be derived from natural or non-natural, ⁇ - or ⁇ -amino acids.
• amino acid residues which are derived from alanine, asparagine, glutamine, glycine, isoleucine, leucine, lysine, ornithine, phenylalanine, proline and valine.
• 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.
• Particularly preferred compounds of Formula Ic are selected from the group con ⁇ sisting of
• AT 1 receptor antagonists are pharmacologically active drug compounds which are capable to selectively block the AT 1 subtype of the angiotensin Il 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, enoltasosarta ⁇ , eprosartan, fonsartan, forasartan, glycyllosartan, irbesar- tan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmis
• 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 1 receptor antagonists.
• Eprosartan is usually used in the form of its mesylate.
• Losartan is usually used in the form of losartan potassium.
• Candesartan is usually used in the form of can- desartan cilexetil.
• 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, caveiprolol, 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.
• alpha2-adrenoceptor agonists including centrally acting alpha2- adrenoceptor agonists, e.g. clonidine, guanfacine, guanabenz methyldopa and moxonidine
• renin-inhbitbirs e.g. alskiren
• ACE-inhbitors e.g.
• mixed ACE/NEP-inhbitors e.g. omapatrilat
• ECE-inhbitors e.g. FR-901533
• PD-069185 CGS- 26303; CGS-34043; CGS-35066; CGS-30084; C
• 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-phenyl-butyric acid ethyl ester; 2-[1-(1- Carboxymethyl ⁇ -oxo ⁇ .S ⁇ . ⁇ -tetrahydro-IH-benzotblazepin-S-ylcarbamoyO-cyclo- pentylmethyl]-4-naphthalen-1-yl-butyric acid ethyl ester; 2-[1-(1-Carboxymethyl-2-oxo- 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-cyclopentylmethyl]-4-phenyl-butyric acid; 2-[1 -(1 -carboxymethyl
• 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 ⁇ Touch-Coupled Device (ILD), IL-VIII, IL-VIII, IL-VIII, IL-VIII, IL-VIII, IL-VIII, IL-VIII, IL-VIII, etc.
• 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.
• 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.
• 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.
• 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.
• 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 eprosartan, daglutril and candesartan or daglutril and losartan are preferred embodi ⁇ ments of the invention.
• 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.
• 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.
• 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.
• 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
• the invention also relates to a kit com ⁇ prising in separate containers in a single package pharmaceutical dosage forms for use in combination, comprising,
• a pharmaceutical dosage form comprising a dually acting compound capable of inhibiting neutral endopeptidase and the endogenous endo ⁇ thelin producing system
• 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.
• 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 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.
• the invention in a third aspect, 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.
• the combination treatment according to the present inven- 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.
• 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.
• a fixed combination of a dually acting compound capable of inhibiting neutral endopeptidase and the endogenous endo- thelin producing system, and an AT-i 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.
• 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:
• ECG electrocardiogram
• AEs vital signs and adverse events
• LVEF left ventricular ejection fraction
• 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.
• an AT r receptor antagonist eprosartan mesylate
• candesartan cilexetil candesartan cilexetil
• 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.
• intended daily doses were 1 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 intraabdominal ⁇ under inhalative halothane anesthesia. A midline abdominal incision was made, and the abdominal aorta was visualized by removal of retroperitoneal fat and connective tissue.
• 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.
• SBP systolic blood pressure
• DBP diastolic blood pressure
• HR heart rate
• ACT locomotor activity
• ACT locomotor activity
• the dosage of the active agents can depend on a variety of factors, such as mode of administration, species, age and/or individual condition. Suitable dosages for the ac ⁇ tive agents of the pharmaceutical combination according to the present invention are therapeutically effective dosages, for example those which are commercially available. Normally, in the case of oral administration, an approximate daily dose of from about 4 mg to about 600 mg is to be estimated for each of the active agents e.g. for a patient of approximately 75 kg in weight.
• a pharmaceutical composition according to the invention may preferably comprise daglutril as dually acting compound capable of inhibiting ECE and hSEP in the range of 5 - 600 mg.
• the dose range of ATi receptor antagonists which are present in the pharmaceutical compositions according to the in ⁇ vention may vary depending on i.a. the substance used and may be (each calculated for the pure active substance, not the salt or solvate thereof), e.g., 4 - 32 mg for candesar- tan, 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 phar ⁇ maceutical composition may occur up to three times a day. Once daily administration forms are preferred.
• Capsules with the following composition per capsule are produced:
• the active agents, the corn starch and the lactose are processed into a homogeneous pasty mixture using ethyl acetate.
• the paste is ground and the resulting granules are placed on a suitable tray and dried at 45°C in order to remove the solvent.
• the dried granules are passed through a crusher and mixed in a mixer with the further following auxiliaries:

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• 2005
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