EP2170895A1 - Sildenafil-n-oxid als prodrug - Google Patents
Sildenafil-n-oxid als prodrugInfo
- Publication number
- EP2170895A1 EP2170895A1 EP08774214A EP08774214A EP2170895A1 EP 2170895 A1 EP2170895 A1 EP 2170895A1 EP 08774214 A EP08774214 A EP 08774214A EP 08774214 A EP08774214 A EP 08774214A EP 2170895 A1 EP2170895 A1 EP 2170895A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- sildenafil
- oxide
- compound
- methyl
- treating
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- Example 3 Pharmacological methods 1 1
- Example 4 Pharmacokinetic and pharmacological test results 12
- This invention relates to the fields of pharmaceutical and organic chemistry, and provides sildenafil N-oxide: 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)- 4-ethoxyphenyl]sulfonyl]-4-methyl-4-oxido-piperazine, having formula (1 A )
- Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE-V)
- sildenafil is selective for PDE-V. Its effect is more potent on PDE-V than on other known phosphodiesterases (10-fold for PDE-VI, >80-fold for PDE-I, >700- fold for PDE-II, PDE-III, PDE-IV, PDE-VII, PDE-VIII, PDE-IX, PDE-X, and PDE-XI.
- the approximately 4, 000-fold selectivity for PDE-V vs PDE-III is important, because PDE-IIl is involved in control of cardiac contractility.
- Sildenafil is only about 10-fold as potent for PDE-V compared to PDE-VI, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
- Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal iso-enzymes.
- the major circulating metabolite results from N- demethylation of sildenafil.
- This metabolite also known as UK 103,320, has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE-V approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.
- N-oxides are known since 1894. By now it is very well known that N-oxides are metabolites of many tertiary amines, and in most cases are also intermediates between tertiary amines and their N-dealkylated analogs. Most, but not all, tertiary amine drugs give rise to N- oxides. This is for instance the case with morphine, imipramine, promazine, cinnarizine and nicotine. How much N-oxidation takes place varies from trace amounts to a nearly quantitative conversion. Some N-oxides were shown to be more potent than their corresponding tertiary amines.
- N-oxides were found to be less potent than their corresponding tertiary amines, and N-oxidation is most commonly regarded to be metabolic deactivation. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines and in other cases the conversion is a mere trace reaction or even completely absent (Bickel, 1969).
- N-oxides and their corresponding tertiary amines are unpredictable. Once formed, N-oxides may be more active than their corresponding tertiary amines, less active or even completely inactive. N-oxides may be reduced to the corresponding tertiary amines or not. When they are, the reaction may be a mere trace or nearly quantitative.
- Sildenafil produces peak plasma concentrations resulting in side effects.
- the most commonly observed adverse events associated with the use of sildenafil include sneezing, headache, flushing, palpitations, dyspepsia, increased intraocular pressure, blurred vision, photophobia, severe hypotension, ventricular arrhythmias, myocardial infarction, stroke, and priapism. These adverse effects can significantly limit the dose level, frequency, and duration of drug therapy.
- Adverse events can be attenuated using special formulations, but different compounds can solve the problem, too. It would thus be desirable to find a compound with the advantages of sildenafil while avoiding its disadvantages.
- Prodrugs have an identical pharmacological profile, but a more favourable pharmacokinetic profile.
- sildenafil-N-oxide acts as prodrug: it is rapidly converted to the parent compound and to N-desmethylsidenafil, an active metabolite of sildenafil
- the invention also relates to pharmacologically acceptable salts, hydrates and solvates of sildenafol N-oxide, which may be substantially free of sildenafil, or a pharmacologically acceptable salt, hydrate or solvate thereof.
- Sildenafil N-oxide can be prepared by oxidizing sildenafil with a suitable oxidizing agent, for instance m-CPBA.
- Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid.
- Sildenafil N-oxides and compositions comprising them are useful in treating affections or diseases effectively treatable — albeit with side effects — with sildenafil: erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH)
- the invention also comprises: pharmaceutical compositions for treating, for example, a disorder or condition treatable by sildenafil, the compositions comprising sildenafil N-oxide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; methods of treating a disorder or condition treatable by sildenafil, the methods comprising administering to a mammal in need of such treating sildenafil N-oxide, or a pharmaceutically acceptable salt thereof; methods of treating a disorder or condition treatable by sildenafil, the methods comprising administering to a mammal in need of such treating sildenafil N-oxide, or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treating a disorder or condition treatable by sildenafil, the compositions comprising sildenafil N-oxide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; methods for treating a disorder or condition treatable by sildenafil, the methods comprising administering to a patient in need of such treating sildenafil N
- the invention also provides the use of sildenafil N-oxide, or a salt thereof, for the manufacture of medicament.
- the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for instance sildenafil or N-demethylsildenafil, for treating one or more of the conditions listed.
- another therapeutic agent or agents for instance sildenafil or N-demethylsildenafil
- Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.
- the invention also provides compounds, pharmaceutical compositions, kits and methods for treating a disorder or condition treatable by sildenafil, the method comprising administering to a patient in need of such treating sildenafil N-oxide or a pharmaceutically acceptable salt thereof.
- the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
- Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
- some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
- compounds of the present invention may be provided substantially free of parent compound 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine (sildenafil).
- substantially free is meant that compound of the present invention contains less than about 50%, 40%, 30%,
- compositions containing sildenafil N-oxide which are substantially free of sildenafil are envisioned in accordance with the present invention.
- Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites.
- Prodrugs are bioreversible 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, permeability, stability, presystemic metabolism and targeting limitations ⁇ Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; Jarvinen, 2005).
- polymorphism is defined as the ability of a compound to exist in more than one crystal form, a so-called polymorph. Polymorphism is a frequently occurring phenomenon. Polymorphism is affected by several crystallization conditions such as temperature, level of supersaturation, the presence of impurities, polarity of solvent, rate of cooling. Polymorphs can be characterized by several methods such as solid state NMR, solubility tests, DSC or melting point determination, IR or Raman spectroscopy. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about”.
- composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
- this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- the term 'combination preparation' comprises both true combinations, meaning an Sildenafil N-oxide or a pharmaceutically acceptable salt thereof, and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising an Sildenafil N-oxide or a pharmaceutically acceptable salt thereof, and sildenafil or another medicament in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
- the pharmacotherapy by definition is simultaneous.
- the contents of 'kit-of-parts' can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Dose recommended treatment dose is the same as for sildenafil: 50 mg, and then lower or raise the dosage as appropriate. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value.
- the dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
- the dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
- the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In general, oral and parenteral dosages will be in the range of 0.1 to 1 ,000 mg per day of total active ingredients.
- terapéuticaally effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic, preventative or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating or preventing the conditions listed herein.
- the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
- pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
- treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) preventing the disease or condition from occurring in a subject predisposed to the disease, but not yet diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing the condition to regress, or (4) stopping the symptoms of the disease.
- the term “medical therapy” intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- Nuclear magnetic resonance spectra ( 1 H NMR and 13 C NMR, APT) were determined in the indicated solvent using a Bruker DRX 600 ( 1 H: 600 MHz, 13 C: 150 MHz) at 300 K, unless indicated otherwise. The spectra were determined in deuterated DMSO, obtained from Cambridge Isotope Laboratories Ltd. Chemical shifts ( ⁇ ) are given in ppm downfield from tetramethylsilane ( 1 H). Coupling constants J are given in Hz.
- Peak shapes in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double quartet), T (triplet), 'dt' (double triplet), 'd' (doublet), 'dd' (double doublet), 's' (singlet), 'bs' (broad singlet) and 'm' (multiplet).
- NH and OH signals were identified after mixing the sample with a drop of D 2 O.
- Flash chromatography refers to purification using the indicated eluens and silica gel (either
- Reactions were monitored by using thin-layer chromatography (TLC) on silica coated plastic sheets (Merck precoated silica gel 60 F254) with the indicated eluens. Spots were visualized by UV light (254 nm) or I 2 .
- TLC thin-layer chromatography
- the LC-MS system consists of 2 Perkin Elmer series 200 micro pumps.
- the pumps are connected to each other by a 50 ⁇ l tee mixer, connected to a Gilson 215 auto sampler.
- the method is as follows:
- step total time flow ( ⁇ l/min) A(%) B(° ⁇
- the auto sampler has a 2 ⁇ l injection loop.
- the auto sampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 ⁇ m particles.
- the column is thermo stated in a Perkin Elmer series 200 column oven at 40° C.
- the column is connected to a Perkin Elmer series 200 UV meter with a 2.7 ⁇ l flowcel.
- the wavelength is set to 254 nm.
- the UV meter is connected to a Sciex API 150EX mass spectrometer.
- the mass spectrometer has the following parameters: Scanrange: 150-900 a.m.u.; polarity: positive; scan mode: profile ; resolution Q1 : UNIT ; step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.
- the light scattering detector is connected to the Sciex API 150.
- the light scattering detector is a Sedere Sedex 55 operating at 50° C and 3 bar N 2 .
- the complete system is controlled by a G3 powermac. Sildenafil and its N-oxide were analyzed in mouse plasma and brain samples using a generic bioanalytical method comprising protein precipitation and HPLC with MS/MS detection.
- Sample preparation Proteins in 100 ⁇ l plasma were precipitated with acetonitrile, and 5 ⁇ l samples of the obtained solution were analyzed. Complete brains were homogenized and centrifuged, and 10 ⁇ l samples of the supernatant were analyzed.
- LC-MS/MS Liquid Chromatography - Tandem Mass Spectrometry
- the human colon model TIM2 (TNO Intestinal Model 2): is a dynamic model for the human large intestine that simulates in vivo conditions. It is an artificial digestive system that has been validated by many studies ⁇ Minekus, 1999).
- Sildenafil N-oxide as well as the pharmacologically acceptable salts thereof, are prodrugs. They are useful in the treatment of diseases effectively treatable — albeit with side effects — with sildenafil: erectile dysfunction (impotence) and pulmonary arterial hypertension
- EXAMPLE 4 PHARMACOKINETIC AND PHARMACOLOGICAL TESTRESULTS
- sildenafil When administered to mice (i.v. or p.o.) sildenafil to a marginal extend is metabolized to its N- oxide: The concentration thereof in the plasma never exceeds 1 - 2% of that of the parent compound, and in brain no trace can be found at all. When sildenafil-N-oxide itself is administered, it is reduced to the parent compound. One hour after i.v. administration of sildenafil-N-oxide, sildenafil concentrations in plasma and brain exceed those of the N-oxide.
- sildenafil-N-oxide 1 mg was inserted into the lumen (120 ml) of the TIM2 model (see above, Minekus, 1999). Samples from the lumen and the dialysate (the latter being a model for the vascular bed of the intestines) were taken at various time intervals, and analyzed for sildenafil-N-oxide and sildenafil: Table 2:
- sildenafil N-oxide was nearly quantitatively reduced to sildenafil. Because many studies validated TIM2 as an in vitro model with high predictive value for the gastrointestinal conditions in living human beings, it is predicted that also in man, after oral administration, sildenafil N-oxide will be reduced to sildenafil: that it will be a prodrug.
- sildenafil As expected, when administered to mice (i.v. or p.o.) sildenafil was metabolized to its N- desmethyl analog, a metabolite that also penetrated the blood-brain barrier, because it was found in brain tissue. New was the observation that when sildenafil-N-oxide was administered, it was also found to be metabolized to N-desmethylsildenafil (only observed after oral dosing).
- sildenafil the data collected in table 5 confirm those known from the scientific literature: the compound is a potent inhibitor of PDE-V, and highly selective for this particular subtype, with the exception of PDE-VI, which is also potently inhibited.
- Sildenafil-N-oxide was found to be 10-fold less potent than sildenafil itself, and showed a comparable selectivity.
- sildenafil-N-oxide acts as prodrug: it is rapidly converted to the parent compound and to N-desmethylsidenafil, a metabolite of sildenafil reported to have about half its potency. It was also found that sildenafil-N-oxide is not completely devoid of activity itself: it has about one tenth of the activity of the parent compound.
- sildenafil N-oxide is formulated into pharmaceutical compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein.
- Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a person skilled in the art from the specification and general knowledge in the art.
- the active ingredient for instance, may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
- compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
- the pharmaceutical formulation contains at least sildenafil N-oxide in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier.
- the total amount of active ingredients suitably is in the range of from about 0.1% (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w). In some embodiments, the amount of active ingredient is greater than about 95% (w/w) or less than about 0.1 % (w/w).
- the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- the mixture may then be processed into granules or pressed into tablets.
- a tablet is prepared using the ingredients below:
- the components are blended and compressed to form tablets each weighing 230 mg.
- the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
- the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
- Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
- Hard gelatin capsules may contain granules of the active ingredients.
- Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents.
- Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
- formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
- container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
- formulations of the present invention in the manufacture of medicaments for use in treating a condition in which inhibition of phosphodiesterases is required or desired, and methods of medical treatment, comprise the administration of a therapeutically effective total amount of sildenafil N-oxide to a patient suffering from, or susceptible to, a condition in which inhibition of phosphodiesterases is required or desired.
- compositions comprising preferred active compounds for systemic use or topical application.
- Other compounds of the invention or combinations thereof may be used in place of (or in addition to) said compounds.
- concentration of the active ingredient may be varied over a wide range as discussed herein.
- the amounts and types of ingredients that may be included are well known in the art.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08774214A EP2170895A1 (de) | 2007-06-26 | 2008-06-23 | Sildenafil-n-oxid als prodrug |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US94619807P | 2007-06-26 | 2007-06-26 | |
EP07111030 | 2007-06-26 | ||
PCT/EP2008/057940 WO2009000798A1 (en) | 2007-06-26 | 2008-06-23 | Sildenafil n-oxide as prodrug |
EP08774214A EP2170895A1 (de) | 2007-06-26 | 2008-06-23 | Sildenafil-n-oxid als prodrug |
Publications (1)
Publication Number | Publication Date |
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EP2170895A1 true EP2170895A1 (de) | 2010-04-07 |
Family
ID=39758764
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP08774214A Withdrawn EP2170895A1 (de) | 2007-06-26 | 2008-06-23 | Sildenafil-n-oxid als prodrug |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP2170895A1 (de) |
KR (1) | KR20100050488A (de) |
AU (1) | AU2008267274A1 (de) |
CA (1) | CA2690294A1 (de) |
EA (1) | EA201070056A1 (de) |
IL (1) | IL202465A0 (de) |
WO (1) | WO2009000798A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2010006227A (es) | 2010-06-07 | 2011-12-14 | World Trade Imp Exp Wtie Ag | Nuevos derivados 1,4-diazepanos, inhibidores de pde-5. |
AT512084A1 (de) | 2011-10-20 | 2013-05-15 | Univ Wien Tech | Diazabicyclo- und diazaspiro-alkanderivate als phosphodiesterase-5 inhibitoren |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999021558A2 (en) * | 1997-10-28 | 1999-05-06 | Vivus, Inc. | Local administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
AU2003205926A1 (en) * | 2002-02-07 | 2003-09-02 | Pfizer Limited | Use of pde5 inhibitors such as sildenafil in the treatment of polycystic ovary syndrome |
-
2008
- 2008-06-23 KR KR1020107001818A patent/KR20100050488A/ko not_active Application Discontinuation
- 2008-06-23 AU AU2008267274A patent/AU2008267274A1/en not_active Abandoned
- 2008-06-23 EA EA201070056A patent/EA201070056A1/ru unknown
- 2008-06-23 CA CA2690294A patent/CA2690294A1/en not_active Abandoned
- 2008-06-23 WO PCT/EP2008/057940 patent/WO2009000798A1/en active Application Filing
- 2008-06-23 EP EP08774214A patent/EP2170895A1/de not_active Withdrawn
-
2009
- 2009-12-02 IL IL202465A patent/IL202465A0/en unknown
Non-Patent Citations (1)
Title |
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See references of WO2009000798A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2009000798A1 (en) | 2008-12-31 |
CA2690294A1 (en) | 2008-12-31 |
KR20100050488A (ko) | 2010-05-13 |
IL202465A0 (en) | 2010-06-30 |
EA201070056A1 (ru) | 2010-06-30 |
AU2008267274A1 (en) | 2008-12-31 |
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