EP1753433A1 - Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v) - Google Patents

Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v)

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Publication number
EP1753433A1
EP1753433A1 EP05747723A EP05747723A EP1753433A1 EP 1753433 A1 EP1753433 A1 EP 1753433A1 EP 05747723 A EP05747723 A EP 05747723A EP 05747723 A EP05747723 A EP 05747723A EP 1753433 A1 EP1753433 A1 EP 1753433A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
inhibitor
group
producing system
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05747723A
Other languages
German (de)
English (en)
Inventor
Dieter Ziegler
Klaus Witte
Matthias Straub
Michael Weske
Dagmar Hoeltje
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
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Filing date
Publication date
Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Priority to EP05747723A priority Critical patent/EP1753433A1/fr
Publication of EP1753433A1 publication Critical patent/EP1753433A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • compositions Comprising NEP-lnhibitors, Inhibitors of the Endogenous Endothelin Producing System and PDE V inhibitors
  • NEP neutral endopeptidase
  • PDE V inhibitor phosphodiesterase 5
  • novel pharmaceutical compositions comprising NEP inhibitors, inhibitors of the endogenous endothelin producing system and PDE V inhibitors and the use of said pharmaceutical composition in the prophylaxis or treatment of cardiovascular diseases in mammals and humans.
  • SD sexual dysfunction
  • vascular diseases such as those associated with hypertension or diabetes mellitus
  • psychiatric disease such as depression.
  • Physiological factors include fear, performance anxiety and interpersonal conflict. SD impairs sexual performance, diminishes selfesteem and disrupts personal relationships thereby inducing personal distress.
  • 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.
  • WO 02/094176 A2 discloses the use of compounds with combined NEP/hSEP inhibitory activity for the prophylaxis or treatment of inter alia cardiovascular diseases.
  • the invention therefore relates in a first aspect to pharmaceutical compositions comprising pharmacologically 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 c) at least one PDE V inhibitor as a third active agent.
  • compositions according to the invention may further and preferably comprise conventional pharmaceutically acceptable auxiliaries and/or earners.
  • 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 z is hydrogen or a a group forming a biolabile carboxylic acid ester and R 3 is a phenyl-Ci- 4 -alkyl group which can optionally be substituted in the phenyl ring by C ⁇ - 4 -alkoxy or halogen; or a naphthyl-C ⁇ - 4 -alkyl group; or b,
  • R 4 is hydrogen or a group forming a biolabile phosphonic acid ester and R ⁇ is hydrogen or a group forming a biolabile phosphonic acid ester; or c,
  • R 7 is hydrogen, C ⁇ - 4 -alkyl or d-4-hydroxyalkyl, the hydroxyl group of which is optionally esterified with C ⁇ -alkanoyl or an amino acid residue
  • R 8 is C ⁇ - 4 -alkyl; C ⁇ - 4 -alkoxy-C ⁇ -4-alkyl; C ⁇ -4-hydroxyalkyl, which is optionally substituted by a second hydroxyl group and the hydroxyl groups of which are each optionally esterified with C 2 _ -alkanoyl or an amino acid residue; (Co- 4 -alkyl) 2 amino-C ⁇ - 8 -alkyl; C 3 - 7 -cycloalkyl; phenyl-d- 4 -alkyl, the phenyl group of which is optionally substituted 1-2 times by C ⁇ - 4 -alkyl, C ⁇ - 4 -alkoxy and/or halogen
  • substituents in the compounds of Formula I are or contain C ⁇ -alkyl groups, these may be straight-chain or branched.
  • 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.
  • substituents contain halogen, fluorine, chlorine or bromine, preferably fluorine or chlorine, are particularly suitable.
  • substituents contain C 2 - 4 -alkanoyl, this may be straight-chain or branched. Acetyl is preferred as C 2 ⁇ -alkanoyl.
  • 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 Chemistry: 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.
  • 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.
  • R 1 , R 2 and R 3 have the above meanings, and physiologically compatible salts of acids of Formula la.
  • Preferred salts of compounds of Formula la are e.g. disclosed in document WO 03/059939 A1 which is incorporated herein by reference.
  • the compounds 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 la may be used.
  • the compounds of Formula la 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 la, are suitable as groups forming biolabile carboxylic acid esters R 1 and R 2 .
  • d-4-alkyl groups in particular methyl, ethyl, n-propyl and isopropyl
  • C ⁇ - 4 -alkyloxy-C ⁇ - 4 -alkyloxy-C ⁇ _ 4 -alkyl groups in particular methoxyethoxy methyl
  • Ca-y-cydoalkyl groups in particular cydohexyl
  • alkyl groups in particular cydopropylmethyl
  • N,N-di-(C (M -alkyl)anr ⁇ ino-C 1 d-4-alkyl groups, in particular methyl, ethyl, n-propyl and isopropyl
  • C ⁇ - 4 -alkyloxy-C ⁇ - 4 -alkyloxy-C ⁇ _ 4 -alkyl groups in particular methoxyethoxy methyl
  • Ca-y-cydoalkyl groups in particular cydohexyl
  • alkyl groups in particular
  • a biolabile ester represents an optionally substituted phenyl-C ⁇ - 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 biolabile ester represents an optionally substituted C 2 - 6 -alkanoyloxy-C 1 _ 4 -alkyl group
  • the C 2-6 -alkanoyl group may be straight-chain or branched.
  • R 1 preferably has the meanings hydrogen, C ⁇ -4-alkyl, p-methoxy benzyl, N,N-di-(C ⁇ M - alkylJamino-C ⁇ -6-alkyl, (RS)-1 -[[(isopropyl)carbonyl]oxy]ethyl, (RS)-1 -[[(ethyl)carbonyl]- oxy]-2-methylpropyl, (RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl, 5-methyl-2-oxo-1 ,3- dioxolen-4-yl-methyl, 2-oxo-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)carbonyl]oxy]ethyl, (RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl, (RS)-1- [[(cydohexyloxy)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.
  • the compounds of Formulas II, III, IV and V are especially suited in their 3S,2'R forms. Most preferred is the compound of Formula II in its 3S,2'R form, also known as "daglutril" or "SLV306".
  • the compounds of Formula la are known, for example, from document EP 0 733 642 A1 which is incorporated herein by reference, and can be produced according to the production processes disdosed or referenced in this document or analogously to said production processes.
  • R 1 , R 4 and R 5 have the meanings given above, or physiologically compatible salts of acids of Formula lb can be used as dually acting compounds capable of inhibiting NEP and the endogenous endothelin producing system.
  • the compounds of Formula lb 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 forming biolabile carboxylic acid esters in compounds of Formula lb are those as specified for compounds of Formula la 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 fundion.
  • 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 alkylene 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 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 I. If R 4 and R s in compounds of the formula lb are not hydrogen and in each case have different meanings, the phosphorus atom of the phosphonic acid group can also be chiral.
  • the invention also relates to the isomer mixtures and isomerically pure compounds of the formula lb formed as a result of chiral phosphorus 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 lb 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 compounds of Formula Ic, for the use as dually acting compounds capable of inhibiting NEP and the endogenous endothelin producing system in pharmacological compositions according 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 document or analogously to said production processes. Where in compounds of Formula Ic the substituents R 7 and/or R 8 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 Formula 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 Formula Ic are those as specified for compounds of Formula la 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 C 2-4 -alkanoyl or an amino acid residue.
  • R 8 has the meaning one or two C_-4-alkyl groups can independently of each other be present.
  • 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; cydopropylmethyl; 2-methoxybenzyl, 4- methoxybenzyl; 4-methoxyphenylethyl; 2,4-dimethoxybenzyl; 1-naphthylmethyl; 3-oxo- 1,1-dimethyl butyl; phenyl-2-oxoethyl; 2-(4-methoxyphenyl)-2-oxoethyl; 3-(2-oxoaze- panyl); (C ⁇ -alkyl) 2 amino-C ⁇ -6 -alkyl I in particular dimethylamino-n-propyl, (methyl)amino- ethyl, amino-n-propy
  • R 7 and R 8 together are C 4 -7-alkylene, the methylene groups of which are optionally 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, omithine, phenylalanine, proline and valine.
  • the compounds can thus be present 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 preferred 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.
  • Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP.
  • PDE V inhibitors will therefore increase and prolong the actions of endogenous substances that signal via the cydic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves.
  • the most widely used PDE V inhibitors have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and have provided a major breakthrough in the treatment of erectile dysfundion in men.
  • PDE V inhibitors which can be used according to the present invention may be selected from the group consisting of avanafil, AWD-12-250, BF/GP- 385, BMS-22313, BMS-341400 , CP-248, CP-461, DA-8159, dasantafil, DMPPO, E- 4021, E-8010, EMD-82639, EMR-62203, exisulind, FR-181074, FR-226807, FR-229934, GF-248, KF-31327, KT-734, LAS-34179, lusupultide, MJ-12504, NCX-911, NM-702, OPC-35564, OSI-461, QAD-171A, roflumilast, SB-96231, Sch-46642, Sch-51866, Sch- 59498, sildenafil, sildenafil citrate, SK-350, SK-3530, SKF-96231, sophoflavescenol, SR
  • Preferred PDE V inhibitors are selected from the group consisting of avanafil, dasantafil, sildenafil, sildenafil citrate, tadalafil, vardenafil and zaprinast, or any physiologically compatible salts, solvates, prodrugs or esters thereof.
  • Sildenafil, sildenafil citrate, tadalafil and vardenafil are more preferred PDE V inhibitors.
  • 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 therapeutical effective amount of the pharmacologically adive agents, alone or in combination with one or more pharmaceutically acceptable auxiliaries and/or carriers, especially suitable for enteral or parenteral application.
  • Pharmaceutical compositions for enteral or parenteral administration are, for example, in unit dosage forms, such as coated tablets, 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.
  • compositions for oral use can be obtained by combining the active compounds 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 formulations 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.
  • the corresponding active agents or their pharmaceutically acceptable salts may also be used in form of their hydrates or include other solvents used for crys- tallization.
  • 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 sildenafil or sildenafil citrate, daglutril and tadalafil, daglutril and vardenafil or daglutril and zaprinast are preferred embodiments of the invention.
  • the active agents (a), (b) and (c) can be obtained and administered in two or more separate unit dosage forms, e.g. in two or more tablets or capsules, the tablets or capsules being physically segregated from each other.
  • the two or more separate unit dosage forms can be administered simultaneously or stepwise (separately), e.g.
  • 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 dually acting compound capable of inhibiting NEP and the endogenous endothelin 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.
  • the PDE V inhibitor 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 formulations 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 dicaicium 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; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfact
  • the invention also relates to a kit comprising 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 pharmaceutical dosage form comprising at least one inhibitor of the endogenous endothelin producing system, or i2) 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 ii) in another separate container a pharmaceutical dosage form comprising at least one PDE V inhibitor.
  • 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 dosage form comprising at least one PDE V inhibitor.
  • 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 adive 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 PDE V inhibitor, for the preparation of a pharmaceutical composition or medicament for the prophylaxis or treatment of sexual dysfunction and/or endothelial dysfunction and/or a cardiovascular disease in mammals and humans.
  • the sexual dysfunction may be a female sexual dysfunction or a male sexual dysfunction. Treatment or prophylaxis of male sexual dysfunction is preferred. Where the sexual dysfunction is male sexual dysfunction, the combination therapy of the present invention is particularly suited to treat or prevent erectile dysfunction, ejaculatory disorders and/or desire disorders. Most preferred is the treatment or prevention of erectile dysfunction.
  • the cardiovascular disease may be selected from angina pectoris; angina abdomi- nalis; arrhythmias; cardiac hypertrophy; congestive heart failure; coronary heart disease; hypertension, in particular essential hypertension, pulmonary hypertension, renal hypertension and/or hypertension associated with obesity, insulin resistance and/or diabetes; myocardial infarction; restenosis and/or stroke.
  • the cardiovascular disease may beselected from essential hypertension, pulmonary hypertension, renal hyperten- sion, hypertension associated with obesity and/or congestive heart failure.
  • the invention in a third aspect, relates to a method of treating or preventing sexual dysfunction and/or endothelial dysfundion and/or a cardiovascular 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 PDE V inhibitor.
  • Subjects in need of such treatments are in particular those humans or mammals who are suffering from or being susceptible to sexual dysfundion and/or endothelial dysfunction and/or a cardiovascular disease.
  • the adive 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 adive 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 ading compound capable of inhibiting neutral endopeptidase and the endogenous endothelin producing system, and an PDE V inhibitor can be used.
  • Fixed combinations comprising daglutril and sildenafil or sildenafil citrate, daglutril and tadalafil, daglutril and vardenafil or daglutril and zaprinast 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 the following test models:
  • the animals received either vehicle (10% arlatone G, 10% ethanol, 80% H 2 O), sildenafil (1 mg/kg), compound of Formula IV (10 ⁇ mol/kg), or a combination of sildenafil + compound of Formula IV intravenously (over 1 min in a total volume of 2 ml/kg body weight). 8 min later, 0.5 nmol/kg Big-ET was infused (over 1 min; Big-ET was from Bachem, Heidelberg). Systolic (SAP) and diastolic arterial blood pressures and heart rate were recorded every 5 min for the next 15 min.
  • vehicle % arlatone G, 10% ethanol, 80% H 2 O
  • sildenafil (1 mg/kg
  • compound of Formula IV 10 ⁇ mol/kg
  • a combination of sildenafil + compound of Formula IV intravenously (over 1 min in a total volume of 2 ml/kg body weight). 8 min later, 0.5 nmol/kg Big-ET was infused (over 1 min; Big-ET was from Bachem, Heidelberg
  • the maximal pressor and bradycardic effects were typically reached within 5 min following Big-ET administration.
  • sildenafil pro- Immediately after administration (and before the Big-ET challenge), sildenafil pro- prised a drop in blood pressure (by 15 ⁇ 3 mm Hg systolic blood pressure as compared to baseline) which was stable for at least 8 min (i.e. until the timepoint of Big-ET applica- tion). This hypotension was not changed when sildenafil was administered in combination with the compound of Formula IV (lowering of blood pressure by 14 ⁇ 4 mm Hg vs. baseline). The compound of Formula IV did thus not reinforce the hypotensive action of sildenafil.
  • Table 1 Effeds of intravenous bolus administration of sildenafil, compound of Formula IV, and combination on maximal Big-ET-induced pressor response
  • results are expressed as mean + SEM of the maximal systolic blood pressures crease (from baseline) observed after the Big-ET challenge (n: number of animals).
  • ambient pressure monitor C11PR, Data Sciences, USA.
  • blood pressure was first monitored for 30 min under baseline (untreated) conditions before a group of animals received sildenafil (3 mg/kg), and another one sildenafil (3 mg/kg) combined with compound of Formula IV (10 ⁇ mol/kg) via injedion into the caudal vein. Blood pressure was then measured for another 30 min.
  • the groups were treated in a cross-over mode, i.e. that - after the 30 min baseline measurement period - the ones that had been treated with sildenafil alone on the previous day were given the combination, and the ones treated with the combination on the day before now received sildenafil alone.
  • the blood pressure (as well as heart rate and adivity values), sampled in 5 min intervals by the Dataquest system, were used for calculation of individual means, i.e. the average blood pressure over the 30 min baseline period, and the average value over the last 15 min of the 30 min interval following the intravenous treatment with compounds.
  • Pretreatment with compound of Formula IV (intravenous bolus, 30 min before sildenafil) caused an even stronger potentiation of the antihypertensive effect of sildenafil (decrease in systolic blood pressure by 33 ⁇ 14 mm Hg).
  • Table 2 Effects of intravenous bolus administration of sildenafil, compound of Formula IV, and combination on systolic blood pressure in SHR
  • the dosage of the adive agents can depend on a variety of fadors, such as mode of administration, species, age and/or individual condition. Suitable dosages for the active agents of the pharmaceutical combination according to the present invention are therapeutical ly effective dosages, for example those which are commercially available. Normally, in the case of oral administration, an approximate daily dose of from about 5 mg to about 600 mg is to be estimated for each of the adive 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 PDE V inhibitors which are present in the pharmaceutical compositions according to the invention may vary depending on i.a. the substance used and may be.
  • the administration of the pharmaceutical 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 adive agents, the corn starch and the ladose 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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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une polythérapie destinée à la prophylaxie et/ou au traitement de la dysfonction sexuelle et/ou de maladies cardio-vasculaires chez des mammifères et des êtres humains et consistant à administrer une combinaison synergique d'au moins un inhibiteur de l'endopeptidase neutre, d'au moins un inhibiteur du système de production de l'endothéline endogène et d'au moins un inhibiteur de la phosphodiestérase 5.
EP05747723A 2004-05-14 2005-05-12 Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v) Withdrawn EP1753433A1 (fr)

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EP05747723A EP1753433A1 (fr) 2004-05-14 2005-05-12 Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v)

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US57082904P 2004-05-14 2004-05-14
EP04102119 2004-05-14
EP05747723A EP1753433A1 (fr) 2004-05-14 2005-05-12 Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v)
PCT/EP2005/052158 WO2005112940A1 (fr) 2004-05-14 2005-05-12 Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v)

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EP05747723A Withdrawn EP1753433A1 (fr) 2004-05-14 2005-05-12 Compositions pharmaceutiques renfermant des inhibiteurs de l'endopeptidase neutre (nep), des inhibiteurs du systeme de production de l'endotheline endogene et des inhibiteurs de la phosphodiesterase 5 (pde v)

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WO2007054975A1 (fr) * 2005-11-08 2007-05-18 Panacea Biotec Ltd Compositions pharmaceutiques destinees au traitement de troubles cardiovasculaires et d'autres troubles associes
PL424453A1 (pl) * 2018-01-31 2019-08-12 Forty-Four Pharmaceuticals Spółka Z Ograniczoną Odpowiedzialnością Sposoby zmniejszania szkodliwego działania niedoboru perfuzji narządów miąższowych przez inhibitory obojętnej endopeptydazy (NEP) i ludzkiej rozpuszczalnej endopeptydazy (hSEP)

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US20020028799A1 (en) * 2000-07-06 2002-03-07 Naylor Alasdair Mark Treatment of male sexual dysfunction
US6991916B2 (en) * 2000-07-14 2006-01-31 Pfizer Inc. Compounds for the treatment of sexual dysfunction
GB0017387D0 (en) * 2000-07-14 2000-08-30 Pfizer Ltd Novel enzyme
WO2002005820A1 (fr) * 2000-07-19 2002-01-24 Lavipharm Laboratories, Inc. Dispersions solides de citrate de sildenafil ayant une forte solubilite dans l'eau
GB0111709D0 (en) * 2001-05-14 2001-07-04 Pfizer Ltd Novel pharmaceuticals
PL367093A1 (en) * 2001-05-18 2005-02-21 Solvay Pharmaceuticals Gmbh Use of compounds with combined nep/mp-inhibitory activity in the preparation of medicaments
SA04250283B1 (ar) * 2003-09-26 2008-05-26 سولفاي فارماسيتيكالز جي أم بي أتش مشتقات من amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid

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