WO2011095553A1 - Stimulateurs de sgc ou activateurs de sgc en combinaison avec des inhibiteurs de pde5 pour le traitement du dysfonctionnement érectile - Google Patents

Stimulateurs de sgc ou activateurs de sgc en combinaison avec des inhibiteurs de pde5 pour le traitement du dysfonctionnement érectile Download PDF

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WO2011095553A1
WO2011095553A1 PCT/EP2011/051576 EP2011051576W WO2011095553A1 WO 2011095553 A1 WO2011095553 A1 WO 2011095553A1 EP 2011051576 W EP2011051576 W EP 2011051576W WO 2011095553 A1 WO2011095553 A1 WO 2011095553A1
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sgc
methyl
phenyl
pde5
trifluoromethyl
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PCT/EP2011/051576
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Peter Sandner
Johannes-Peter Stasch
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Bayer Schering Pharma Aktiengesellschaft
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine

Definitions

  • the present invention relates to soluble guanylate cyclase (sGC) and to phosphodiesterases (PDEs) and the pharmacology of sGC stimulators, sGC activators and PDE inhibitors. More particularly, the invention relates to the use of sGC stimulators and sGC activators in combination with PDE5 inhibitors for preparation of medicaments for the treatment of male erectile dysfunction (MED) in particular for the MED treatment of difficult to treat patients and patients not or not fully responding to PDE5 inhibitors.
  • MED male erectile dysfunction
  • cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • PDE5 inhibitors could be useful for the treatment of symptomatic BPH which is characterized by Overactive Bladder (OAB) and Lower Urinary Tract Symptoms (LUTS) (Porst et al. 2007, Koehler and McVary 2008). But most strikingly and well established is the effect of cGMP on penile function.
  • OAB Overactive Bladder
  • LUTS Lower Urinary Tract Symptoms
  • Nitric oxide during either direct or psychogenic sexual stimulation, is synthesized by neuronal NO synthase (nNOS) in the nerve terminals of parasympathetic, non-adrenergic, non-cholinergic (NANC) neurons in the penis and also by endothelial NO synthase (eNOS) in the endothelial cells of the blood vessels and the lacunar spaces of the corpora cavernosa activates smooth muscle cell soluble guanylate cyclase (sGC).
  • nNOS neuronal NO synthase
  • NANC non-adrenergic
  • eNOS endothelial NO synthase
  • sGC smooth muscle cell soluble guanylate cyclase
  • cGMP Relaxation of arterial smooth muscle is accompanied by increased blood flow to the penile corpora and an enlargement of the cavernosal tissue finally resulting penile erection.
  • the level of cGMP is regulated by its rate of synthesis via guanylate cyclase (sGC) and its hydrolysis to the physiologically inactive GMP by the cGMP-hydrolyzing phosphodiesterases.
  • sGC guanylate cyclase
  • PDE5 is the most prominent in the human corpus cavernosum and inhibition of PDE5 leads to an increase in the level of cGMP.
  • heme-dependent sGC stimulators such as BAY 41-2272 according to compound of the formula (2), BAY 41-8543 according to compound of the formula (1), and BAY 63-2521 according to compound of the formula (3)
  • heme-independent sGC activators such as BAY 58-2667 according to compound of the formula (5), and HMR-1766 according to compound of the formula (6), (for review see Evgenov et al., 2006).
  • sGC stimulators such as YC-1 (Ko et al. 1994, Mizusawa et al. 2002), BAY 41- 2272 (Stasch et al. 2001), A-350619 (Miller et al. 2003) or BAY 63-2521 (Munter et al. 2002) were pre-clinically investigated.
  • the sGC stimulator BAY 41-2272 could relax human and rabbit cavernosal tissues in vitro (Kalsi et al. 2003, Baracat et al. 2003).
  • sGC stimulators and sGC activators i.e. BAY 60-4552 could elicit significant erections in rabbits and rats in the range of vardenafil (Example 1).
  • sGC stimulators and sGC activators i.e. BAY 60-4552 as a stand alone treatment produced a substantial decrease in blood pressure in rabbit and rats (Example 5) limiting the use of sGC stimulators and sGC activators as stand alone.
  • PDE5 inhibitors have not only additive but over-additive effects on penile erection in animal models in rabbits and rats. In these models PDE5 inhibitors do not work and sGC stimulators and sGC activators have only moderate efficacy.
  • the combination avoid the haemodynamic side effects by using only a low- dose sGC stimulator component.
  • the optimal proportions of the single components, the sGC stimulators or sGC activators and the PDE5 inhibitor in the combination could be already identified.
  • the preferred dosis ranges are 0.1 mg to 1 mg of sGC stimulator or sGC activator and 2.5 to 20 mg PDE5 inhibitor.
  • a preferred dosis is 1 mg of sGC stimulator or sGC activator and 10 mg PDE5 inhibitor.
  • Another preferred dosis is 1 mg of sGC stimulator or sGC activator and 20 mg PDE5 inhibitor.
  • Another preferred dosis is 0.5 mg of sGC stimulator or sGC activator and 10 mg PDE5 inhibitor.
  • Another preferred dosis is 0.5 mg of sGC stimulator or sGC activator and 20 mg PDE5 inhibitor.
  • Urological disorders addressed by therapeutic agents of the invention which in particular and with substantial advantage can be treated by the above mentioned sGC stimulators or sGC activators in combination with PDE5 inhibitors, are genitourinary disorders comprising Male Sexual Dysfunction (MED).
  • MED Male Sexual Dysfunction
  • MED is defined by "the inability to achieve and/or maintain a penile erection for satisfactory sexual performance" (NIH Consensus Development Panel on Impotence, 1993)"
  • MED refers further to patients with mild, moderate and severe MED.
  • MED refers also to MED caused by i.e. psychogenic, organic, vascular, endocrino logic, neurogenic, arteriogenic, drug-induced, fibrotic origin.
  • MED refers also to ejaculatory disorders such as premature ejaculation (PE), anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD).
  • PE premature ejaculation
  • HSDD hypoactive sexual desire disorder
  • combinations of specific sGC stimulators or sGC activators with PDE5 inhibitors have an substantial advantage in regard to hypotensive side effects over methods of treatment already known in the art, i.e. NO-donors, sGC stimulators or sGC activators.
  • the invention provides sGC stimulators or sGC activators in combination whith PDE5 inhibitors which are useful for the treatment of urological disorders especially MED, and superior in efficacy over methods of treatment already known.
  • the invention provides sGC stimulators or sGC activators in combination whith PDE5 inhibitors which are useful for the treatment of urological disorders especially MED, and superior in the side effect profile over methods of treatment already known.
  • the invention provides sGC stimulators or sGC activators in combination whith PDE5 inhibitors which are useful for the treatment of urological disorders especially MED in which the sGC stimulator or sGC activator is dosed in the same range then the PDE5 inhibitor and is dosed down to 1/10 and/or 1/20 of the dose of the PDE5 inhibitor.
  • the invention provides sGC stimulators or sGC activators in combination whith PDE5 inhibitors which are useful for the treatment of urological disorders especially MED in which the dosis range of sGC stimulator or sGC activator is 0.1 to 1 mg and the dosis range of PDE5 inhibitor is 2.5 to 20 mg.
  • the first study with the combined administration of a sGC stimualtor and a PDE5 inhibitor was performed in healthy male subjects.
  • Guanylate cyclase (sGC) stimulator and sGC activator is preferably a compound selected from the group consisting of
  • Compounds (1), (2), (3), (4) are known soluble guanylate cyclase (sGC) stimulators which have been previously described for the treatment of stable angina pectoris or erectile dysfunction.
  • sGC soluble guanylate cyclase
  • PDE-5 inhibitors which are useful for the combined treatment of urological disorders are in particular Tadalafil ((6R,12aR) -2,3,6,7,12,12a - Hexahydro - 2 - methyl - 6 - (3,4-methylene -dioxyphenyl) pyrazino(l ',2': 1 ,6) pyrido(3,4-b)indole- 1 ,4-dione), Vardenafil (2-(2-Ethoxy-5-(4-ethylpiperazin- 1 -yl- l-sulfonyl)phenyl)-5-methyl-7-propyl-3H-imidazo (5, 1-f) (l ,2,4)triazin-4-one), Sildenafil (3-[2- ethoxy-5-(4-methylpiperazin-
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral e.g., intravenous, intradermal, subcutaneous' oral (e.g.' inhalation)' transdermal (topical) transmucosal and rectal administration.
  • Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyetheylene glycol, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as maitol sorbitol sodium chloride in the composition.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or conl starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or conl starch
  • a lubricant such as magnesium stearate or sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g.' a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Bio degradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • the invention provides sGC stimulators or sGC activators in combination with PDE5 inhbitiors and their use for the preparation of pharmaceutical compositions for MED, whereby these combinations comprise either i) pharmaceutical compositions comprising a compound having a sGC stimulatory or activatory action and PDE-5 inhibitory activity, or ii) pharmaceutical compositions comprising one sGC stimulator and sGC activator and at least one PDE-5 inhibitor as a fixed combination in one application unit, or iii) a kit of parts containing at least two sets of pharmaceutical compositions, each set consisting of at least one pharmaceutical preparation comprising a PDE-5 inhibitor in units of at least one dose and at least one pharmaceutical preparation comprising a sGC activator or sGC stimulator in units of at least one dose, whereby each application unit of said pharmaceutical compositions is administered in combination, sequentially, as single dose or in multiple doses.
  • the present invention provides: A pharmaceutical composition for the treatment of a disease comprised in a group of diseases consisting of MED, especially of mild, moderate and severe MED containing at least one compound selected from
  • Tadalafil ((6R,12aR) -2,3,6,7,12,12a - Hexahydro - 2 - methyl - 6 - (3,4-methylene -dioxyphenyl) pyrazino(l',2':l,6) pyrido(3,4-b)indole-l,4-dione), Vardenafil (2-(2-Ethoxy-5-(4-ethylpiperazin-l-yl- l-sulfonyl)phenyl)-5-methyl-7-propyl-3H-imidazo (5,1-f) (l,2,4)triazin-4-one), Sildenafil (3-[2- ethoxy-5-(4-methylpiperazin-l-yl)sulfonyl-phenyl]-7-methy-l-9-propyl-2,4,7,8-tetrazabicyclo
  • a sGC stimulator and activator for the preparation of a pharmaceutical composition for the treatment of a disease comprised in a group of diseases consisting of MED, especially of mild, moderate and severe MED
  • sGC stimulator or activator selected from the group of sGC stimulators and activators of 2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,44o]pyridin-3 -yl] -5-(4-morpholinyl)-4,6-pyrimidinediamine( 1 ), 2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-(4-pyridinyl)-4-pyrimidinamine (2), methyl-4,6-diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl- (methyl)carbamate (3), methyl-4,6-diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]
  • a pharmaceutlical composition as mentioned above for the stimulation and activation of the soluble guanylate cyclase in a mammal having a disease comprised in a group of diseases consisting of MED, especially of mild, moderate and severe MED
  • sGC stimulators and sGC activators i.e. BAY 60-4552 alone and in combination with PDE5 inhibitors, i.e. Vardenafil were tested in vivo, in 3 animal models (Example 1 , 2, 3, 4) in which PDE5 inhibitors are ineffective.
  • sGC stimulators and sGC activators i.e. BAY 60- 4552 alone and in combination with PDE5 inhibitors, i.e. Vardenafil were tested in vivo on hemodynamic effects in conscious animals (Expample 5).
  • Combinations of sGC stimulators and sGC activators, i.e. BAY 60-4552 with PDE5 inhibitors, i.e. vardenafil are efficacious in PDE5-inhibitor-resistant ED in in vivo models in rabbits and rats
  • Combinations of sGC stimulators and sGC activators, i.e. BAY 60-4552 with PDE5 inhibitors, i.e. vardenafil showed more than additive effects in PDE5-inhibitor-resistant ED models in vivo in rabbits and rats (Example 3).
  • the sGC stimulators and sGC activators, i.e. BAY 60-4552 as a stand alone treatment produced a substantial decrease in blood pressure in rabbit and rats.
  • Combinations of sGC stimulators and sGC activators, i.e. BAY 60-4552 with PDE5-inhibitors, i.e. vardenafil do not show additive or more than additive effects on blood pressure in rabbits and rats (i.e. Example 5).
  • Combinations of sGC stimulators and activators, i.e. BAY 60-4552 with PDE5 inhibitors, i.e. vardenafil are safe, with a hemodynamic profile similar to vardenafil.
  • the preferred embodiment of the invention is a combination of at least one sGC stimulator or activator selected from the group comprising of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin- 3-yl]-5-(4-pyridinyl)-4-pyrimidina m i n e ( 2 ) , m e t h y l-4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[l-(2- fluorobenzyl)-lH
  • Another preferred embodiment of the invention is a combination according to claim 1 in which the sGC activator is l- ⁇ 6-[5-chloro-2-( ⁇ 4-trans-4- ⁇ trifluoromethyl)cyclohexyl]benzyl ⁇ oxy)phenyl] pyridin-2-yl ⁇ -5-(trifluoromethyl)-lH-pyrazole-4-c arb oxylic aci d ( 8 ), l-[6-(2-(2-methyl-4-(4- trifluoromethoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid (9), l [6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-lH-pyrazole-4-caboxylic acid (10), l-( ⁇ 2-[3 -chloro-5-(trifluoromethyl)phenyl] -5-methyl- 1
  • Another preferred embodiment of the invention is a combination as disclosed above in which the PDE5 inhibitor is Vardenafil or Sildenafil.
  • Another preferred embodiment of the invention is a combination according to claims 1 to 3 for the use as a medicament.
  • Another preferred embodiment of the invention is the use of a combination as disclosed above for the manufacture fo a medicament for the treatment of Male Sexual Dysfuntion (MED).
  • MED Male Sexual Dysfuntion
  • Another preferred embodiment of the invention is a combination as disclosed above for the use in Sexual Dysfuntion (MED).
  • MED Sexual Dysfuntion
  • Another preferred embodiment of the invention a the use of a combination as disclosed above for the manufacture fo a medicament for the treatment of Male Sexual Dysfuntion (MED) in cases where the patient suffers form a PDE5 inhibitor resistance.
  • MED Male Sexual Dysfuntion
  • Another preferred embodiment of the invention is a combination as disclosed above for the use in Male Sexual Dysfuntion (MED) in cases where the patient suffers form a PDE5 inhibitor resistance.
  • MED Male Sexual Dysfuntion
  • Another preferred embodiment of the invention is a pharmaceutical formulation comprising at least one combination as disclosed above.
  • Another preferred embodiment of the invention is a pharmaceutical formulation comprising at least one combination as disclosed above for the use in Male Sexual Dysfuntion (MED).
  • Another preferred embodiment of the invention is a pharmaceutical formulation comprising at least one combination as disclosed above for the use in Male Sexual Dysfuntion (MED) in cases where the patient suffers form a PDE5 inhibitor resistance.
  • the conscious rabbit ED model previously described was used for the investigation of Erectile function.
  • conscious male chinchilla rabbits (3 -4kg) were orally treated with the test compounds or with vehicle via gavage, followed by i.v. injection of the NO- donnor sodium nitro-prusside (SNP) in the ear vein, 90 minutes after oral applications.
  • SNP NO- donnor sodium nitro-prusside
  • the SNP injections were done in a high dose setting (0.2mg/kg SNP i.v) and a low dose setting (0.02mg/kg SNP i.v.) corresponding to the general ED-population and the PDE5 non-responder ED-population, respectively.
  • Penile length was quantified in 5 minutes intervals after injection of the SNP.
  • the rectile function was measured after oral application of the test compounds, i.e. vehicle, PDE5 inhibitors, i.e. vardenafil, sGC stimulators, i.e. BAY 60-4552. or combinations of PDE5 inhibitors, i.e. vardenafil with sGC stimulators i.e. BAY 60-4552.
  • the FDC containing lmg/kg vardenafil and 0.1 mg/kg BAY 60-4552 produced still relevant erections which were higher than that of BAY 60-4552 as a stand alone treatment (not shown). These data indicate the overadditive effects of combinations of the sGC stimulator i.e. BAY 60-4552 and the PDE5 inhibitor i.e Vardenafil on penile function. These results also indicate the superiority over PDE5 inhibitor or sGC stimulator or sGC activator stand-alone treatment therapy.
  • Intracavemosal pressure reflectiong penile erection was measured as described previously (Giuliano et al. 1993 , Sandner 2008b).
  • Male Wistar Rats 150-250g were anaesthetized with isolfurane, after laparotomy a pressure catheter is implanted in the corpus cavernosum and the cavernous nerve is carefully prepared for electric field stimulation (EFS).
  • EFS electric field stimulation
  • the intracavernous pressure is registered via a pressure transducer (MLT0698) and amplified and stored with the PowerLab® system.
  • MKT0698 pressure transducer
  • PowerLab® PowerLab®
  • L-NAME 3mg/kg bolus i.v blocking the NO synthases was performed to induce ED. 10 Minutes after injection of L-NAME test compounds (Placebo, BAY 60-4552, Vardenafil and the combination) were applied.
  • Example 4 Patients after radical prostatectomy do not respond to PDE5 inhibitors since the cavernous nerves are at least partly destroyed and removed during surgery resulting in the inability to produce NO and induce cGMP elevation in the corpus cavernosum. This nerve crush could be mimicked in anaesthetized rats generating an ED model for the difficult to treat ED-population not, or not fully, responding to PDE5 inhibitor treatment. Bilateral cavernous nerve crush injury resulted in a significant erectile dysfunction if compared to
  • a PDE5 inhibitor i.e. Vardenafil (lmg/kg p.o.) produced a low decrease in mean arterial blood pressure (-4mmHg) accompanied by an increase in heart rat (+14 bpm).
  • the sGC stimulator i.e. BAY 60-4552 stand-alone dose dependently produced a decrease in blood pressure of -5, -11, -22 mmHg in the 1, 3 and lOmg/kg dose respectively, which was accompanied by heart rate increase of +24, +51 and +103 bpm.
  • BAY 60-4552 produced a blood pressure decrease of -3 and -4 mmHg and heart rate increase of +7 and +24 bpm in the combination of of 1+0.1 and 0.3+0.3 mg/kg respectively.
  • the increase in efficacy of the FDC in ED function was not accompanied by haemdoynamic side effects compared with vardenafil ( Figure 5).
  • the conscious rabbit ED model previously described was used for the investigation of Erectile function as described in Example 1.
  • the SNP injections were done in a high dose setting (0.2mg/kg SNP i.v) corresponding to the general ED-population in which PDE5 inhibitors are fully active. Penile length was quantified in 5 minutes intervals after injection of the SNP.
  • the erectile function was measured after oral application of the test compounds, i.e. vehicle, PDE5 inhibitors, i.e. vardenafil, or combinations of PDE5 inhibitors, i.e. vardenafil with sGC stimulators, i.e. BAY 60-4552.
  • PDE5 inhibitors i.e.
  • vardenafil and combinations of PDE5inhibitors and sGC stimulators or activators i.e. vardenafil + BAY 60-4552 showed a similar range of efficacy which was on the upper-end of the effects which could be seen in these experiments.
  • the conscious rabbit ED model as described in Expample 1 and Example 6 was used for assessment of responderrates.
  • the SNP injections were done in a high dose setting (0.2mg/kg SNP i.v) corresponding to the general ED-population in which PDE5 inhibitors are fully active.
  • Penile length was quantified in 5 minutes intervals after injection of the SNP.
  • "Non response" was defined as penile length ⁇ 5 mm during the whole observation perios after the SNP injection.
  • Penile length was quantified after treatment with PDE5 inhibitors, i.e. vardenafil, sildenafil, tadalafil, or the combination of an sGC stimulator or sGC activator, i.e. BAY 60-4552 with and PDE5 inhbitior, i.e. vardenafil.
  • Figure 1 NO-dependent efficacy of the PDE5 inhibitor vardenafil Qmg/kg p.o.) and the sGC stimulator BAY 60-4552 ( 3 ⁇ 4mg/kg and
  • Figure 2A Effects of PDE5 inhibitor vardenafil, sildenafil, tadalafil, the sGC stimulator BAY 60- 4552 and combinations of vardenafil and BAY 60-4552 penile erection at low SNP (0.02mg/kg i.v.) in conscious male rabbits.
  • Figure 2B Effects of PDE5 inhibitor vardenafil, sildenafil, tadalafil, the sGC stimulator BAY 60- 4552 and combinations of vardenafil and BAY 60-4552 penile erection at low SNP (0.02mg/kg i.v.) in conscious male rabbits.
  • Figure 3 The effect of BAY 60-4552 and vardenafil Fixed dose combination (0.03 mg/kg Vardenafil i.v. + 0.03 or 0.01 mg/kg BAY 60-4552 i.v., respectively) on intracavernousal pressure (ICP) in L- NAME treated anaesthetized rats with ED. Data are mean + SEM.
  • Figure 4 The effect of BAY 60-4552 and vardenafil fixed dose combination (0.03 mg/kg BAY 60-
  • Figure 5 Effects of vehicle (Placebo), the PDE5 inhibitor vardenafil, the sGC stimulator BAY 60- 4552 and combinations of vardenafil and BAY 60-4552 [in mg/kg p.o.] on heart rate (upper panel) and mean arterial blood pressure (lower panel). Data are mean + SEM.
  • Figure 6 Effects of the PDE5 inhibitor vardenafil and sildenafil and combinations of vardenafil and BAY 60-4552 on penile erection at high SNP (0.2mg/kg i.v.) in conscious male rabbits.

Abstract

La présente invention concerne la guanylate cyclase soluble (sGC) et les phosphodiestérases (PDE) et la pharmacologie des stimulateurs de sGC, activateurs de sGC et inhibiteurs de PDE. Plus particulièrement, l'invention concerne l'utilisation de stimulateurs de sGC et activateurs de sGC en combinaison avec des inhibiteurs de PDE5 pour la préparation de médicaments pour le traitement du dysfonctionnement érectile chez l'homme (MED) en particulier pour le traitement d'un MED chez des patients difficiles à traiter et des patients ne répondant pas ou ne répondant pas entièrement aux inhibiteurs de PDE5.
PCT/EP2011/051576 2010-02-05 2011-02-03 Stimulateurs de sgc ou activateurs de sgc en combinaison avec des inhibiteurs de pde5 pour le traitement du dysfonctionnement érectile WO2011095553A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9353090B2 (en) 2014-07-22 2016-05-31 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acids as activators of soluble guanylate cyclase
USRE46886E1 (en) 2012-09-07 2018-06-05 Boehringer Ingelheim International Gmbh Alkoxy pyrazoles as soluble guanylate cyclase activators
US10208018B2 (en) 2014-07-02 2019-02-19 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
US10316020B2 (en) 2015-12-18 2019-06-11 Novartis Ag Indane derivatives and the use thereof as soluble guanylate cyclase activators

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
DE10002200A1 (de) * 2000-01-19 2001-07-26 Christian Stief Behandlung von Sexualfunktionsstörungen mit Stimulatoren der Guanylatzyclasen als Monotherapie oder in Kombination mit Phosphodiesterase-Hemmern
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
US20040087591A1 (en) * 1996-11-01 2004-05-06 Garvey David S. Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use
WO2008124505A2 (fr) * 2007-04-05 2008-10-16 Ironwood Pharmaceuticals,Inc. Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides
WO2008138483A1 (fr) * 2007-05-12 2008-11-20 Bayer Schering Pharma Aktiengesellschaft Stimulateurs de la sgc, activateurs de la sgc et combinaisons pour le traitement de troubles urologiques
WO2009032249A1 (fr) 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009068652A1 (fr) 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
WO2009071504A1 (fr) 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble
WO2009123316A1 (fr) 2008-04-04 2009-10-08 武田薬品工業株式会社 Dérivé hétérocyclique et son utilisation
WO2010081647A2 (fr) * 2009-01-17 2010-07-22 Bayer Schering Pharma Aktiengesellschaft Stimulateurs sgc d'activateurs sgc en combinaison avec des inhibiteurs pde5 dans le traitement du dysfonctionnement érectile

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040087591A1 (en) * 1996-11-01 2004-05-06 Garvey David S. Phosphodiesterase inhibitors and nitric oxide donors, compositions and methods of use
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
DE10002200A1 (de) * 2000-01-19 2001-07-26 Christian Stief Behandlung von Sexualfunktionsstörungen mit Stimulatoren der Guanylatzyclasen als Monotherapie oder in Kombination mit Phosphodiesterase-Hemmern
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2008124505A2 (fr) * 2007-04-05 2008-10-16 Ironwood Pharmaceuticals,Inc. Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides
WO2008138483A1 (fr) * 2007-05-12 2008-11-20 Bayer Schering Pharma Aktiengesellschaft Stimulateurs de la sgc, activateurs de la sgc et combinaisons pour le traitement de troubles urologiques
WO2009032249A1 (fr) 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009068652A1 (fr) 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
WO2009071504A1 (fr) 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble
WO2009123316A1 (fr) 2008-04-04 2009-10-08 武田薬品工業株式会社 Dérivé hétérocyclique et son utilisation
WO2010081647A2 (fr) * 2009-01-17 2010-07-22 Bayer Schering Pharma Aktiengesellschaft Stimulateurs sgc d'activateurs sgc en combinaison avec des inhibiteurs pde5 dans le traitement du dysfonctionnement érectile

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
BARACAT JS; TEIXEIRA CE; OKUYAMA CE ET AL.: "Relaxing effects induced by the soluble guanylyl cyclase stimulator BAY 41-2272 in human and rabbit corpus cavernosum", EUR. J. PHARMACOL, vol. 477, no. 2, 2003, pages 163 - 169
BISCHOFF E; SCHRAMM M; STRAUB A ET AL.: "BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide-dependent penile erection in vivo", UROLOGY, vol. 61, 2003, pages 464 - 467
BISCHOFFE, SCHNEIDER K.: "A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection", INT. J. IMPOT. RES., vol. 13, 2001, pages 230 - 235, XP009013375, DOI: doi:10.1038/sj.ijir.3900703
DE TEJADA IS: "Therapeutic strategies for optimizing PDE5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat", INT J IMPOT RES, vol. 216, 2004, pages 40 - 42
EVGENOV OLEG V ET AL: "NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential", NATURE REVIEWS. DRUG DISCOVERY, NATURE PUBLISHING GROUP, GB, vol. 5, no. 9, 1 September 2006 (2006-09-01), pages 755 - 768, XP002534424, ISSN: 1474-1776, DOI: DOI:10.1038/NRD2038 *
EVGENOV OV; PACHER P; SCHMIDT PM ET AL.: "NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential", NAT REV DRUG DISCOV, vol. 5, no. 9, 2006, pages 755 - 68, XP002530645, DOI: doi:10.1038/nrd2038
GIULIANO F; BERNABE J; JARDIN A ET AL.: "Antierectile role of the sympathetic nervous system in rats", J. UROL., vol. 150, 1993, pages 519 - 524
KALSI JS; RALPH DJ; MADGE DJ ET AL.: "A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats", INT. J. IMPOT. RES., vol. 16, 2004, pages 479 - 485
KO FN; WU CC; KUO SC ET AL.: "YC-1, a novel activator of platelet guanylate cyclase", BLOOD, vol. 84, no. 12, 1994, pages 4226 - 4233, XP000878904
KOHLER TS; MCVARY KT: "The Relationship between Erectile Dysfunction and Lower Urinary Tract Symptoms and the Role of Phosphodiesterase Type 5 Inhibitors", EUR. UROL., 4 September 2008 (2008-09-04)
LUE TF: "Erectile dysfunction", NEW ENG. J. MED., vol. 342, 2000, pages 1802 - 1813
MIINTER K; WEIGAND S; BISCHOFFE: "BAY 63-2552: Its Effect on Penile Erections in Concious Rabbits", BSP-PHARMA REPORT PH 32390, 2002
MILLER LN; NAKANE M; HSIEH GC ET AL.: "A-350619: a novel activator of soluble guanylyl cyclase", LIFE SCI., vol. 72, no. 9, 2003, pages 1015 - 1025, XP002500588, DOI: doi:10.1016/S0024-3205(02)02361-5
MIZUSAWA H; HEDLUND P; BRIONI JD ET AL.: "Nitric oxide independent activation of guanylate cyclase by YC-1 causes erectile response in rat", J. UROL., vol. 167, no. 5, 2002, pages 2276 - 2281
PORST H; SANDNER P; ULBRICH E.: "Vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia", CURR. UROL. REP., vol. 9, 2008, pages 295 - 301
SANDNER P.: "Efficacy and safety of the sGC stimulator BAY 60-4552 alone and in combination with the PDE5 inhibitor vardenafil (BAY 38-9456) for the treatment ofPDE5-resistant Erectile Dysfunction", BSP-PHARMA-REPORT IN PREPARATION, 2008
SANDNER P.: "Efficacy of the fixed dose combination of the sGC stimulator BAY 69-4552 in combination with the PDE5 inhibitor vardenafil (BAY 38-9456) in rat ED models", BSP-PHARMA-REPORT IN PREPARATION, 2008
SANDNER P.; SVENSTRUP N.; TINEL H. ET AL.: "PDE5 inhibitors and erectile dysfunction (ED). Expert Opin", THER. PATENTS, vol. 18, 2007, pages 21 - 33
SANDNER P; HIITTER J; TINEL H ET AL.: "PDE5 inhibitors beyond erectile dysfunction", INT. J. IMPOT. RES., vol. 19, no. 6, 2007, pages 533 - 543, XP009134960, DOI: doi:10.1038/sj.ijir.3901577
SCHULTHEISS D; STIEF CG: "Physiology and pathophysiology of erection: consequences for present medical therapy of erectile dysfunction", ANDROLOGIA, vol. 31, no. 1, 1999, pages 59 - 64
SHABSIGH R: "Therapy of ED: PDE-5 Inhibitors", ENDOCRINE, vol. 23, 2004, pages 135 - 141
SHABSIGH R; SEFTEL AD; ROSEN RC ET AL., UROLOGY, vol. 68, pages 689 - 696
STASCH JP; BECKER EM; ALONSO-ALIJA C ET AL.: "NO-independent regulatory site on soluble guanylate cyclase", NATURE, vol. 8, 2001, pages 212 - 215

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46886E1 (en) 2012-09-07 2018-06-05 Boehringer Ingelheim International Gmbh Alkoxy pyrazoles as soluble guanylate cyclase activators
US10208018B2 (en) 2014-07-02 2019-02-19 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
US10550102B2 (en) 2014-07-02 2020-02-04 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
US9353090B2 (en) 2014-07-22 2016-05-31 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acids as activators of soluble guanylate cyclase
US10316020B2 (en) 2015-12-18 2019-06-11 Novartis Ag Indane derivatives and the use thereof as soluble guanylate cyclase activators

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