EP1753432A1 - Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle - Google Patents

Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle

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Publication number
EP1753432A1
EP1753432A1 EP05743154A EP05743154A EP1753432A1 EP 1753432 A1 EP1753432 A1 EP 1753432A1 EP 05743154 A EP05743154 A EP 05743154A EP 05743154 A EP05743154 A EP 05743154A EP 1753432 A1 EP1753432 A1 EP 1753432A1
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EP
European Patent Office
Prior art keywords
receptor agonists
endopeptidase
inhibitors
antagonists
agents
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Withdrawn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
EP05743154A
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German (de)
English (en)
Inventor
Dieter Ziegler
Klaus Witte
Matthias Straub
Michael Weske
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Abbott Products GmbH
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Solvay Pharmaceuticals GmbH
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Priority to EP05743154A priority Critical patent/EP1753432A1/fr
Publication of EP1753432A1 publication Critical patent/EP1753432A1/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Withdrawn legal-status Critical Current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

  • NEP neutral endopeptidase
  • hSEP human soluble endopeptidase
  • the invention relates to a novel pharmaceutical combination composition comprising at least one NEP inhibitor, at least one inhibitor of hSEP and at least one compound supportive to the inventive use as specified in more detail below.
  • 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.
  • WO 02/094176 A2 it is known that certain compounds, including those disclosed in document EP 0 733 642 A1 and in document EP 0 916 679 A1, may inhibit the metalloprotease enzyme IGS5.
  • WO 02/094176 A2 discloses the use of compounds with combined NEP- and hSEP-inhibitory activity for the prophylaxis or treatment of inter alia cardiovascular diseases.
  • It is the object of the present invention to provide a novel therapy for the prophylaxis and/or treatment of SD, in particular male sexual dysfunction ( MSD) in mammals and humans.
  • MSD male sexual dysfunction
  • a dually acting compound capable of inhibiting NEP and hSEP is particularly suitable in the prophylaxis or treatment of SD. It has further been found that a pharmaceutical composition which comprises at least one NEP inhibitor, at least one hSEP inhibitor and at least one further compound supportive to the inventive use provides specific advantages in the prophylaxis ad/or treatment of SD.
  • the invention therefore relates in a first aspect to the use of a dually acting compound capable of inhibiting NEP and hSEP for the prophylaxis or treatment of sexual dysfunction. More specifically, a compound of general Formula I,
  • R 1 is hydrogen or a group forming a biolabile carbonic acid ester
  • A represents a group selected from the subgroups a, R 3
  • R 2 is hydrogen or a a group forming a biolabile carbonic acid ester and R 3 is a phenyl-C ⁇ - 4 -alkyl group which can optionally be substituted in the phenyl ring by group or b,
  • 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, and/or physiologically compatible salts of acids of Formula I can be used according to the invention.
  • substituents in the compounds of Formula I are or contain groups, these may be straight-chain or branched and contain preferably 1 to 2 carbon atoms and are preferably methyl or methoxy. 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 contain halogen, fluorine, chlorine or bromine, preferably fluorine or chlorine, are particularly suitable.
  • the compounds of Formula I 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.
  • Suitable physiologically compatible salts of dicarboxylic acids or monoesters 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.
  • the compounds of Formula la contain two chiral carbon atoms, namely the carbon atom which is in the 3 position of the ring framework and bears the amide side-chain, and the carbon atom of the amide side-chain which bears the radical R 3 .
  • the compounds can therefore exist in several optically active stereoisom- eric forms or as a racemate. 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 .
  • C 1- -alkyl groups in particular methyl, ethyl, n-propyl and isopropyl; C ⁇ -4 -alkyloxy-C ⁇ -4-alkyloxy-C ⁇ . 4 -alkyl groups, in particular methoxyethoxy methyl; C ⁇ -cycloalkyl groups, in particular cyclohexyl; C 3 .7-cycloalkyl-C1.4- alkyl groups, in particular cyclopropylmethyl; N.N-dKCo- A -alky amino-Ci- ⁇ -alkyl groups; phenyl or phenyl-C 1-4 -alkyl groups optionally substituted in the phenyl ring once or twice by halogen, chain bonded to two adjacent carbon atoms; dioxolanyl methyl groups optionally substituted in the dioxolane ring by C ⁇ .
  • biolabile ester represents an optionally substituted phenyl-C ⁇ -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-chlorobenzyi.
  • 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 -e-alkanoyloxy-C ⁇ -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-methoxybenzyl, N,N-di-(Co-4- alkylJamino-Ci- ⁇ -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- [[(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.
  • the lower alkylene chain of the phenyl-d- 4 -alkyl group may contain preferably 1 to 2 carbon atoms.
  • R 3 is an optionally substituted phenethyl group which can optionally be substituted one or two times by halogen, or d. 4 -alkyl, or is a naphthylethyl group.
  • the compounds of Formula la most preferred are the compounds which are 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 [alternative name: 3-[1- ⁇ 2'-(ethoxycarbonyl) ⁇ -4'-phenylbutyl]-cyclopentan-1-carbonylamino]- 2 l 3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1 -acetic acid] of Formula II,
  • 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 disclosed or referenced in this document or analogously to said production processes.
  • R 1 , R 4 and R 5 have the meanings given above, and physiologically compatible salts of said acids of Formula lb can be used according to the invention.
  • 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.
  • Suitable groups R 1 forming biolabile carboxylic acid esters 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 function.
  • groups which are suitable for this purpose are lower alkyl groups, C 2 -C e -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 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 5 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.
  • the compounds of the invention are suited for the prophylaxis or treatment of SD.
  • SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (see Melman, A. & Gingell, J. C. (1999).
  • FSD female sexual dysfunction
  • MSD male sexual dysfunction
  • the dually acting compounds of the invention which are capable of inhibiting NEP and hSEP are particularly beneficial for the prophylaxis and/or treatment of MSD (e. g. male erectile dysfunction-MED).
  • a further advantage of compounds of Formula I in this indication is a certain ECE inhibitory share at their profile of action.
  • MED is defined as: “... the inability to achieve and/or maintain a penile erection for satisfactory sexual performance (see NIH Consensus Development Panel on Impotence (1993). NIH Consensus Conference Impotence. JA. M. A. 270: 83) .".
  • FSD is best defined as the difficulty or inability of a woman to find satisfaction in sexual expression.
  • FSD is a collective term for several diverse female sexual disorders (Leiblum, S. R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106 ; Berman, J. R., Berman, L.& Goldstein, I. (1999).
  • Female sexual dysfunction Incidence, pathophysiology, evaluations and treatment options. Urology, 54,385-391.). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems.
  • Several types of disease, medications, injuries or psychological problems can cause FSD.
  • FSD FSD-related disorders
  • the categories of FSD are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (Leiblum, S. R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106).
  • Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli.
  • Arousal is the genital response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal blood flow, vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity.
  • Orgasm is the release of sexual tension that has culminated during arousal, hence, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm.
  • FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders.
  • the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), in doing so they may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders.
  • a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder, more preferably for the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder, and sexual pain disorder, and preferably in the treatment or prophylaxis of sexual arousal disorder.
  • Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies.
  • This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.
  • FSAD is characterised by inadequate genital response to sexual stimulation.
  • the gen ' italia do not undergo the engorgement that characterises normal sexual arousal.
  • the vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded.
  • Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis.
  • SSRIs selective serotonin re-uptake inhibitors
  • Sexual pain disorders includes dyspareunia and vaginismus
  • the prevalence of FSD is difficult to gauge because the term covers several types of problems, some of which are difficult to measure, and because the interest in treating FSD is relatively recent.
  • FSD farnesoid styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene, a component of vasculogenic dysfunction (e.g. FSAD) contributing to the overall female sexual complaint. There are at present no drugs licensed for the treatment of FSD.
  • FSAD vasculogenic dysfunction
  • Empirical drug therapy includes oestrogen administration (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspirone or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects. Since interest is relatively recent in treating FSD pharmacologically, therapy consists of the following: psychological counseling, over-the-counter sexual lubricants, and investigational candidates, including drugs approved for other conditions. These medications consist of hormonal agents, either testosterone or combinations of oestrogen and testosterone and more recently vascular drugs, that have proved effective in MED. None of these agents has yet been demonstrated to be effective in treating FSD.
  • DSM Diagnostic and Statistical Manual
  • FSAD The Diagnostic and Statistical Manual
  • the arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia.
  • the disturbance causes marked distress and/or interpersonal difficulty.
  • Studies investigating sexual dysfunction in couples reveals that up to 76% of women have complaints of sexual dysfunction and that 30-50% of women in the USA experience FSD (Berman, J. R., Berman, L. A., Werbin, T. J. et al. (1999).
  • FSAD hormone replacement therapy
  • the present invention therefore in a second aspect provides a method of treating or preventing sexual dysfunction in mammals and humans comprising administering to a subject in need thereof an effective amount of a dually acting compound capable of inhibiting NEP and hSEP according to the invention.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight, sex and response of the particular patient.
  • a therapeutically effective daily oral or intravenous dose of the agents of the present invention is likely to range from 0.01 to 50 mg/kg body weight of the subject to be treated, preferably 0.01 to 20 mg/kg, more preferably 0.1 to 20 mg/kg.
  • the agents of the present invention may also be administered by intravenous infusion, at a dose which is likely to range from 0.001-10 mg/kg/hr.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the present invention is advantageous as it helps provide a means for restoring a normal sexual arousal response-namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity.
  • the present invention provides a means to restore, or potentiate, the normal sexual arousal response.
  • the genital organs consist of an internal and external group.
  • the internal organs are situated within the pelvis and consist of ovaries, the uterine tubes, uterus and the vagina.
  • the external organs are superficial to the urogenital diaphragm and below the pelvic arch. They comprise the mons pubis, the labia majora and minora pudendi, the clitoris, the vestibule, the bulb of the vestibule, and the greater vestibular glands" (Gray's Anatomy, C. D. Clemente, 13th American Edition).
  • R. J. Levin teaches that, because "...
  • penile erection is a haemodynamic event which is dependent upon the balance of contraction and relaxation of the corpus caver- nosal smooth muscle and vasculature of the penis (see Lerner, S. E. et al (1993). A review of erectile dysfunction: new insights and more questions. J. Urology 149: 1246- 1255).
  • Corpus cavernosal smooth muscle is also referred to herein as corporal smooth muscle or in the plural sense corpus cavernosa. Relaxation of the corpus cavernosal smooth muscle leads to an increased blood flow into the trabecular spaces of the corpus cavernosa, causing them to expand against the surrounding tunica and compress the draining veins.
  • NANC non-adrenergic, non-cholinergic
  • NO nitric oxide
  • CGRP calcitonin gene related peptide
  • VIP VIP
  • NOS nitric oxide synthase
  • reducing corporal smooth muscle tone may aid NO to induce relaxation of the corpus cavernosum.
  • NO is released from neurones and the endothelium and binds to and activates soluble guanylate cyclase (sGC) located in the smooth muscle cells and endothelium, leading to an elevation in intracellular cyclic guanosine 3", 5'-monophosphate (cGMP) levels.
  • sGC soluble guanylate cyclase
  • CNP C-type natriuretic peptide
  • GC-B membrane-bound guanylyl cyclase B
  • Stimulation of GC-B leads to an increase in intracellular cGMP and, consequently, smooth muscle relaxation.
  • PDE5-inhibitors e.g. sildenafil increase intracellular cGMP in corpus cavernosum tissue by inhibiting its breakdown.
  • PDE5-inhibitors are inactive in the absence of a stimulator of cGMP formation, e.g. in the absence of NO.
  • VIP positive nerve fibres have been found in the trabecular meshwork of the corpus cavernosum, suggesting a role of VIP release in penile erection. Effects of VIP are thought to be mediated via increases in cAMP and are thus complementary to those of cGMP-elevating agents.
  • VIP intracavernosal injection of VIP (combined with the ⁇ -adrenoceptor antagonist phentolamine) was found to be a safe and effective treatment, with a response rate of 67% (erections sufficient for sexual intercourse).
  • the endopeptidases NEP and hSEP both degrade CNP and VIP and thereby limit the effects of CNP and VIP on cavernosal smooth muscle.
  • Enzymes a) hSEP (sol hu)(his)6; or: His6-tagged hSEP ectodomain.
  • stock solution 53 ⁇ g/ml in 20 mM HEPES pH 7.2, 5% glycerol, 0.005% Tween20, 100 mM NaCI, purity >99% working solution: stock solution diluted with assay buffer to 5 ⁇ g/ml Supplier: Innogenetics, Ghent, Belgium. Preparation and purification of the protein were performed as described in WO 02/094176.
  • NEP prepared from pig kidney cortex
  • stock solution 120 ⁇ g/ml in 20 mM bisTris, purity >95% working solution: stock solution diluted with assay buffer to 5 ⁇ g/ml Supplier: Dr. Philippe Crine, Univ. of Montreal, Canada
  • Substrates a) VIP b) CNP (32-53) stock solution: 100 ⁇ M in assay buffer Supplier: Bachem, Weil am Rhein, Germany
  • Assay buffer 100 mM Tris pH 7.0, 250 mM NaCI All test compounds were dissolved in DMSO at 10 mM and further diluted with assay buffer.
  • assay buffer 80 ⁇ l of assay buffer, 10 ⁇ l of enzyme working solution (NEP or hSEP) and 10 ⁇ l of pep- tide stock solution (VIP or CNP) were mixed in an Eppendorf vial and incubated for 120 min. at 37 °C. The enzymatic reaction was subsequently terminated by heating to 95 °C for 5 min. After centrifugation (Heraeus Biofuge B, 3 min) the supernatant was subjected to HPLC.
  • enzyme working solution NEP or hSEP
  • VIP or CNP pep- tide stock solution
  • a reversed phase HPLC technique with a CC 125/4 Nucleosil 300/5 C 18 RP column and a CC 8/4 Nucleosil 100/5 C18 precolumn (Macherey-Nagel, D ⁇ ren, Germany) was used. 60 ⁇ l of the reaction samples were injected into the HPLC and the column was eluted at a flow rate of 1 ml/min with the following gradient:
  • test compounds according to the invention were able to prevent degradation of CNP and VIP by both NEP and SEP.
  • the respective IC 50 -values for inhibition of breakdown are given below in table 2.
  • the compound thiorphan has also been tested as a reference standard for selective inhibition of NEP.
  • Organ chambers were maintained at 37°C and continuously bubbled with 95% O2 and 5% CO 2 to maintain a pH at 7.4.
  • the cavernosal strips were connected to force transducers for isometric tension recording (Pioden controls Ltd, UK), and an initial tension of 1g was applied. Following amplification, the tension changes were digitalized via a Mac LabTM/ 8 using Chart software (AD Instruments Ltd).
  • the tissue preparation were allowed to equilibrate for 90 minutes, while being washed periodically (every 15 minutes) with fresh Krebs-HEPES buffer. When a stable resting tension was attained, the strips were set to at least 500 mg of basal tension.
  • the erectile tissues were primed with KCI 80 mM during 10 min. Once this priming period was achieved, the strips were washed by fresh Krebs-HEPES solution and allowed to re- equilibrate for 30 minutes at 500 mg of tension.
  • the strips were incubated with one of the following compounds (all at 10 ⁇ M, unless indicated otherwise) during 20 min: compound of Formula IV, compound of Formula V, SM-19712 (a selective and potent endothelin converting enzyme-1 inhibitor), DL-thiorphan (a selective and potent NEP inhibitor), and the combination of SM-19712, 10 ⁇ M and DL-thiorphan, and the common vehicle (phosphate buffer).
  • compound of Formula IV compound of Formula V
  • SM-19712 a selective and potent endothelin converting enzyme-1 inhibitor
  • DL-thiorphan a selective and potent NEP inhibitor
  • the combination of SM-19712, 10 ⁇ M and DL-thiorphan and the common vehicle (phosphate buffer).
  • Contractile responses were expressed as absolute change in maximal developed tension (in mg). To reduce the potential heterogeneity of responses between strips, the contraction to big-ET-1 was normalized by the contractile responses to KCI 80 mM obtained during the priming period.
  • results are from duplicate or triplicate determinations from a single corpus cavernosum sample were averaged and values are expressed as percentage of the contractile responses induced by 80 mM of KCI, as mean + SEM, for n corpus cavernosum samples.
  • ET-1 induces a potent, slowly developing, and long-lasting contraction of penile arteries and the corpus cavernosum and may, thereby, contribute to keeping the penis in a flaccid state (see Andersson, K.-E. (2003) Erectile physiological and pathophysiological pathways involved in erectile dysfuncton. J Urol. 170:S1-S6). Recently, it has been shown that plasma levels of ET-1 are elevated in patients with erectile dysfunction compared to healthy controls. Moreover, ET-1 levels were the best independent predictors of erectile dysfunction in men without cardiovascular risk factors (see Bocchio M. et al.
  • the present invention also provides a pharmaceutical composition containing the dually acting inhibitors of NEP and of hSEP for the treatment of sexual dysfunction.
  • the present invention provides a pharmaceutical combination composition for the prophylaxis or treatment of SD, said pharmaceutical composition comprising pharmacologically effective quantities of each of a) at least one neutral endopeptidase inhibitor, b) at least one inhibitor of human soluble endopeptidase and c) at least one compound supportive to the inventive use which is selected from the group consisting of the specific compounds or subgroups of PDE5 inhibitors, NPY receptor antagonists, PDE2 inhibitors, nitric oxide donors, dopamine receptor agonists, melanocortin receptor agonists, potassium channel openers, calcium activated potassium channel openers, ⁇ 1-adrenoceptor antagonists, VIP receptor agonists or VIP analogues, ⁇ 2-adrenoceptor antagonists, estrogens, medroxyprogesterone, medroxyprogesterone acetate, oestrogens, methyl testosterone hormone replacement therapy agents, testosterone, testosterone replacement agents, testosterone/oestradiol agents, estrogen agonist
  • a dually acting compound capable of inhibiting NEP and hSEP as subcombination of at least one neutral endopeptidase inhibitor (a) and at least one inhibitor of human soluble endopeptidase (b) can be used.
  • Most preferred in this regard is the use of a compound of Formula I, more particular the use of a compound of Formula la.
  • the pharmaceutical combination compositions of the present invention comprise as component c) one or more other pharmaceutically active agents supportive to the inventive use, such as a NEP inhibitor, one or more of a PDE5 inhibitor (e. g.
  • sildenafil, varde- nafil and/or IC351 one or more of NPY receptor antagonist, one or more of a PDE2 inhibitor, one or more of a nitric oxide (NO) donor (e. g. NMI-921), one or more of a dopamine receptor agonist (e. g. apomorphine, Uprima, Ixsene), one or more of a melanocortin receptor agonist (e. g. Melanotan II orPT14), one or more of a potassium channel opener (e. g. a KATP channel opener (e. g. minoxidil, nicorandil) and/or a calcium activated potassium channel opener (e. g.
  • a potassium channel opener e. g. a KATP channel opener (e. g. minoxidil, nicorandil) and/or a calcium activated potassium channel opener (e. g.
  • BMS204352 one or more of an ⁇ -adrenoceptor antagonist (e. g.phentolamine, Vasofem, Vasomax), one or more of a VIP receptor agonist or a VIP analogue (e. g. Ro-125-1553) or VIP fragments, one or more of a ⁇ - adrenoceptor antagonist with VIP combination (e. g. Invicorp, Aviptadil), one or more of a o-2-adrenoceptor antagonist (e. g.
  • HRT especially Pre- marin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Prempro, Prempak, Premique, Estratest, Estratest HS, Tibolone), one or more of a testosterone replacement agent (including DHEA (dehydroandrostendione), testosterone (Tostrelle) or a testosterone implant), one or more of a testosterone/oestradiol agent, one or more of an estrogen agonist (e. g. Lasofoxifene), one or more of a serotonin receptor agonist or antagonist (e. g.
  • Preferred components c) are PDE5 inhibitors.
  • the compounds of the present invention can be administered alone, they will frequently be administered in admixture with a pharmaceutical earner, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the components a), b) and c) of the pharmaceutical combination compositions can be administered jointly or consecutively in either order.
  • the agents of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), or solubilising agent(s).
  • the pharmaceutical compositions or the pharmaceutical combination compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
  • the pharmaceutical compositions or the pharmaceutical combination compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • the pharmaceutical compositions or the pharmaceutical combination compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • the daily dosage level of the agents of the present invention may typically be from 10 to 500 mg (in single or divided doses).
  • tablets or capsules may contain from 5 to 600 mg of active agent for administration singly, or two or more at a time, as appropriate.
  • oral administration of the agents of the present invention is the preferred route, being the most convenient and can in some cases avoid disadvantages associated with other routes of administration-such as those associated with intracavemosal (i. c.) administration.
  • the drug may be administered parenterally.
  • the pharmaceutical compositions - which may be for human or animal usage will comprise any one or more of a pharmaceutically acceptable diluent, carrier or excipient.
  • the agent of the present invention is typically administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • compositions may comprise as, or in addition to the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s) or solubilising agent(s).
  • the invention also comprises a kit, comprising in separate containers in a single package pharmaceutical compositions for use in combination which comprises, a) in one separate container a pharmaceutical composition comprising at least one neutral endopeptidase inhibitor and in a second separate container a pharmaceutical composition comprising at least one inhibitor of human soluble endopeptidase, or b) in one separate container a pharmaceutical composition comprising a dually acting compound capable of inhibiting neutral endopeptidase and human soluble endopeptidase, and c) in another separate container a pharmaceutical composition comprising at least one compound supportive to the inventive use which is selected from the specific compounds or subgroups of PDE5 inhibitors, NPY receptor antagonists, PDE2 inhibitors, nitric oxide donors, dopamine receptor agonists, melanocortin receptor agonists, potassium channel openers, calcium activated potassium channel openers, ⁇ 1-adrenoceptor antagonists, VIP receptor agonists or VIP analogues, o2- adrenocept
  • a kit
  • the active substance, the corn starch and the lactose were thickened with the 10% gelatine solution.
  • the paste was comminuted and the resulting granules were placed on a suitable sheet and dried at 45°C.
  • the dried granules were fed through a crushing machine and mixed with the following further adjuvants in a mixer:
  • Purified water 4,948.00 mg The solids were dissolved in water, the solution was sterilised and was poured into ampoules in portions of 5 ml each.
  • compositions of compounds according to the invention are known from e.g. documents WO 03/068266 A1 or WO 03/059939 A1.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation médicinale de composés à action double capables d'inhiber l'endopeptidase neutre (= NEP) et l'endopeptidase humaine soluble (= hSEP) dans la prophylaxie et/ou le traitement de la dysfonction sexuelle chez des mammifères et des êtres humains.
EP05743154A 2004-05-14 2005-05-12 Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle Withdrawn EP1753432A1 (fr)

Priority Applications (1)

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EP05743154A EP1753432A1 (fr) 2004-05-14 2005-05-12 Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle

Applications Claiming Priority (4)

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US57082904P 2004-05-14 2004-05-14
EP04102119 2004-05-14
PCT/EP2005/052156 WO2005112939A1 (fr) 2004-05-14 2005-05-12 Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle
EP05743154A EP1753432A1 (fr) 2004-05-14 2005-05-12 Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle

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EP1753432A1 true EP1753432A1 (fr) 2007-02-21

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EP05743154A Withdrawn EP1753432A1 (fr) 2004-05-14 2005-05-12 Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle
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
GB0017387D0 (en) * 2000-07-14 2000-08-30 Pfizer Ltd Novel enzyme
US6991916B2 (en) * 2000-07-14 2006-01-31 Pfizer Inc. Compounds for the treatment of sexual dysfunction
EP1301186A1 (fr) * 2000-07-19 2003-04-16 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
BR0209855A (pt) * 2001-05-18 2004-06-15 Solvay Pharm Gmbh Uso de compostos com atividade inibidora de nep/mp combinada na preparação de medicamentos
SA04250283B1 (ar) * 2003-09-26 2008-05-26 سولفاي فارماسيتيكالز جي أم بي أتش مشتقات من amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid

Non-Patent Citations (2)

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Title
MCDOWELL ET AL: "The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides", BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, vol. 43, no. 3, - 1997, pages 329 - 332 *
See also references of WO2005112939A1 *

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WO2005112939A1 (fr) 2005-12-01
EP1753433A1 (fr) 2007-02-21

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