TW200918533A - Sildenafil N-oxide as prodrug - Google Patents

Abstract

The invention concerns sildenafil N-oxide as prodrug, to pharmaceutical compositions containing this compound, to methods for preparing it, and methods for preparing compositions. The invention relates to 1-[[3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4, 3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl-4-oxido-piperazine having formula (1A) and pharmacologically acceptable salts, hydrates and solvates thereof. The invention also relates to uses of the compound, and compositions containing it, particularly for the manufacture of medicaments useful in the treatment of affections or diseases effectively treatable-albeit with side effects- with sildenafil.

Description

200918533 IX. INSTRUCTIONS: FIELD OF THE INVENTION The present invention relates to the field of pharmaceuticals and organic chemistry and provides sildenafil N-5 oxide: 1-[[3-(6,7-dihydro-) having the following formula (1A) 1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl Base _4- oxygen bridge bottom. Qin

And a pharmaceutical composition comprising the compound, a process for preparing the compound, 10 and a process for preparing the composition. BACKGROUND OF THE INVENTION Sildenafil is a potent and selective inhibitor of type 5 cGMP-specific phosphodiesterase (PDE-V)

1-[4-Ethoxy_3_(6,7-dihydrosuccinemethyl_7_oxo_3_propyl_m_pyrazolo[4,3_d]. 密定_5_基) Benzosulfonyl]_4_methylpiperazine, sildenafil (Ep 〇 463 756) 200918533 In vitro studies have shown that sildenafil is selective for PDE-V. It is more potent against PDE-V than other known phosphodiesterases (1〇 for PDE-VI; 8〇 for PDE-I; for pdE-II, PDE-III, PDE) -IV, PDE-VII, PDE-VIII, PDE-IX, PDE-X and PDE-XI, 5 > 700 times. The approximately 4,000-fold selectivity for PDE-V relative to PDE-m' is important. Because PDE-III is involved in the control of cardiac contractility, sildenafil is only about 10-fold more potent than PDE-VI, an enzyme found in the retina associated with the phototransduction pathway of the retina. This lower selectivity is believed to be the basis for anomalies associated with color visual observations observed at higher doses or plasma levels. Sildenafil is primarily composed of CYP3A4 (primary pathway) and CYP2C9 (secondary pathway). The liver is said to be cleared by granules. The main loop metabolite is produced by N-demethylation of sildenafil. This metabolite, also known as UK 103,320, has PDE selectivity properties similar to sildenafil and PDE-V is an in vitro potency of approximately 5% of the parent drug. 15 The plasma concentration of this metabolite is approximately 40% of the plasma concentration seen for sildenafil. Thus, the metabolite accounts for approximately 2% of the pharmacological effects of sildenafil. N-oxides have been known since 1894. It is now generally accepted that the oxides are metabolites of many tertiary amines and, in most cases, Intermediates between tertiary amines and their N-de-alkylated analogs. Most, but not all, tertiary amines 20 produce N-oxides such as morphine, imipramine, promazine, cinnarizine and smoke. This is the case with alkalis. The amount of N-oxidation that occurs varies from trace to near-quantitative conversion. Some N-oxides show stronger action than their corresponding tertiary amines. The most famous example of them is librinine (Librium®). One of the most commonly used drugs in psychosis and general medicine. However, in many cases, N_oxides are found to be weaker than their corresponding 200918533 tertiary amines, and N-oxidation is most commonly considered a metabolic loss. Although it is easy to reduce the N-oxides to their corresponding tertiary amines by chemical means, this occurs to varying degrees in the human body. Some N-oxides can undergo almost quantitative reduction conversion to become corresponding Tertiary amine In other cases, the conversion is only a trace of 5 traces, or even completely absent (Bickel, 1969). Therefore, the formation of N-emulsifiers and their corresponding tertiary amines is unpredictable. Once formed, n_oxidation The materials may be more active, less active or even completely inactive than their corresponding tertiary amines. The N-oxides may be reduced to the corresponding tertiary amines or may not. When they are available, the reaction may be traces only or Close to quantitative. 10 Since Paracelsus ('s〇la dosls facit venenum'), it is generally accepted that the treatment and toxic effects of drugs are related to their concentration at the relevant target site. Since the latter is generally not readily available, plasma levels are used as an approximation of the concentration of the relevant drug. In the development of lie, a window of suitable concentration is defined to provide a lower or lower bound of efficacy, and an upper boundary where side effects begin to become apparent. Ideally, the two concentration gaps are so large that it is easy to administer the drug in a manner that is effective but does not produce side effects. In fact, it is almost impossible to be ideal forever' and most drugs show side effects. In most cases, the occurrence of side effects may be related to the peak blood concentration, which exceeds the lower limit level associated with side effects. 2 〇 (4) That does not produce a guide (4) peak blood t concentration. The most commonly observed adverse events associated with the use of sildenafil include sneezing, headache, flushing, dysfunction, indigestion, elevated intraocular pressure, blurred vision, photophobia, severe hypotension, and Arrhythmia, myocardial infarction, stroke and abnormal erection of the penis. These adverse effects may significantly limit the dose level, frequency, and duration of drug therapy between 200918533 to reduce adverse events using a particular formulation, but different compounds can also resolve the 4 problem. Therefore, it is desirable to find the advantages of sildenafil while avoiding its deficiency. Prodrugs have the same scholastic properties but have more favorable pharmacokinetic properties. 5 SUMMARY OF THE INVENTION Summary of the Invention When administered orally, sildenafil _N_oxide is filled with the current drug: it rapidly turns into the parent D and converts to the demethyl-sildenafil, ie, Active metabolite of diazepam

The present invention also relates to pharmacologically acceptable salts, hydrates and solvates of sildenaza oxide which may be substantially free of sildenafil or a pharmacologically acceptable salt, hydrate or solvent. Compound. Sildenafil N. Oxide can be prepared by oxidizing sildenafil with a suitable oxidizing agent such as m_CPBA. The pharmaceutically acceptable salts can be obtained by mixing the compounds of the present invention with a suitable acid, such as a mineral or organic acid, using standard procedures well known in the art, such as by 200918533. Sildenafil N-oxides and compositions comprising the same can be used to treat conditions or diseases in which sildenafil can be effectively treated (even with side effects): erectile dysfunction 5 impotence (impotence) and pulmonary hypertension (PAH) The invention further comprises: a pharmaceutical composition for treating, for example, a disorder or condition treatable by sildenafil, the composition comprising sildenafil N-oxide or a pharmaceutically acceptable salt thereof and a pharmaceutical An acceptable carrier; 10 a method of treating a disorder or condition treatable by sildenafil comprising administering to a mammal in need of such treatment a sildenafil N-oxide or a pharmaceutically acceptable amount thereof Salt; a method of treating a disorder or condition treatable by sildenafil, the method comprising administering a simiana heterooxide or a pharmaceutically acceptable salt thereof to a Wei animal in need of such treatment; A pharmaceutical composition comprising a sildenafil N-oxide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, by a pharmaceutical composition of a sildenafil treatment disorder or condition; Defensin treatment or Process conditions, which process comprises 2〇 patient in need of such treatment a pharmaceutically sildenafil or a pharmaceutically acceptable salt, heteroaryl oxides. The invention also provides a sildenide oxide or its use in the manufacture of a medicament. The present invention relates to combination therapy wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, of 200918533, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered simultaneously or sequentially or as another Therapeutic agents (therapeutic agents), such as a combination formulation of West, Nafia or N-desmethylsildenafil, are administered to treat one or more of the conditions listed. Such other therapeutic agents can be administered prior to, concurrently with, or subsequent to administration of the compound of the invention. The present invention also provides chemotherapeutic treatments, pharmaceutical compositions, kits and methods for overcoming disorders or conditions in the treatment of Western materials, the method comprising administering sildena to a patient in need of such treatment. An oxide or a pharmaceutically acceptable salt thereof. The invention also provides processes for the preparation of the compounds of the invention and intermediates useful in those processes. Some of the crystalline forms of the compounds may exist as polymorphs: they are considered to be themselves in the present invention. Furthermore, it is also within the scope of the invention for some compounds to form solvates with water (i.e., hydrates) or conventional organic solvents. 15 Isotope-labeled sildenafil oxime-oxide or a pharmaceutically acceptable salt thereof (detectable by PET or SPECT) is also within the scope of the invention. The above conditions are also used for the general formula (3) using [13q-, [14c]_, [3h]-, [18f]-, bucket]_ or other isotopically enriched atomic labels suitable for receptor binding or metabolic studies. Compound 0 20 found that incidental events in which sildenafil N-oxides can be used as prodrugs offer the possibility of using these compounds as alternatives, with the clinical benefit of prolonging the duration of action and attenuating peak blood concentration, thereby Improved side effect performance. Thus, in some embodiments of the invention, substantially free of the parent may be provided: the compound 1-[4_ethoxy[3-(6,7.:hydroindolyl-7-oxo-3propyl) |対 and 200918533 [4,3 -d]. The compound of the present invention is a benzoyl sulfonyl group of phenylene sulfonate (sildenafil). By substantially free is meant that the compound of the invention comprises less than about 50%, 40%, 30%, 20%, 1%/0, 1%, 〇5% of sildenafil or within the detection limit. It does not contain western materials as impurities. According to the invention, a pharmaceutical composition comprising Westin 5 that is substantially free of sildenafil is contained. Any compound that defines metabolism in the body to provide a bioactive agent (i.e., sildenafil) is a prodrug within the scope and spirit of the present application. Prodrugs are therapeutic agents that are themselves inactive but are converted to one or more active metabolites. A prodrug is a bioreversible derivative of a drug that is used to overcome some of the obstacles encountered with the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism, and dry-direction limitation 799 VII//α, 2004; Ettmayer, 2004; Mrvinen, 2005). The term "polymorphism" is defined as the ability of a compound to exist in more than one crystal form (the polymorph of 15). Polymorphism is a common phenomenon. Polymorphism is affected by several crystallization conditions such as temperature, level of supersaturation, presence of impurities, polarity of the solvent, and rate of cooling. Polymorphs can be characterized by several methods such as solid state NMR, solubility testing, DSC or melting point determination, IR or Raman spectroscopy. 20 In order to provide a more concise description, some of the quantitative expressions given herein are not limited by the term “about”. It should be understood that regardless of whether or not the term "about" is used explicitly, each quantity given herein is intended to mean the value that is actually given, and also means an approximation of the value of such a given value, which will be based on the ordinary skill in the art. It is reasonably derived to include the values of nearly 11 200918533 caused by the test and/or measurement conditions given by such values. In the entire description of this shed book and the scope of the patent, the word "contains" Shou „ hai „ The only form of s] such as "comprising ((7) mprising), and "comprising (c〇m (4)), does not exclude the intention of other additives, components, integers or steps. The term "composition" as used herein encompasses The product of the specified ingredients of the Sister Lake, and any product obtained directly or indirectly by combining the specified amounts of the specified ingredients. As for the drug, and the term 'this term' encompasses any one or more active ingredients and inert ingredients. The product of the carrier, as well as by combining, complexing or agglomerating any two or more components 'either by dissociating one or more components, or by other types of one or more components Any product obtained directly or indirectly by reaction or interaction. A pharmaceutical composition is prepared by subjecting the active ingredient to a liquid carrier or a finely divided solid carrier or a combination of both, and if If necessary, the product is formed into a desired preparation. The pharmaceutical composition includes sufficient active target compound to produce a desired effect on the course or condition of the disease. Accordingly, the pharmaceutical composition of the present invention encompasses by contacting the compound of the present invention An acceptable carrier is any composition prepared by the combination of 15. In the context of the present application, the term 'combination formulation, includes both true combinations, ie, the sildenafil team physically combined in m丨 such as a tablet or injectable towel. Oxygen: or an acceptable salt thereof, and other _, including the 'kit of parts', including sildenafil 2 in a separate dosage form or acceptable for its manufacture. a salt, and sildenafil or another agent, and instructions for use, optionally with means for facilitating the administration of the compound of the component, such as a private label or a map. The drug treatments occur simultaneously according to the definition. The contents of the 'package kit' can be administered simultaneously or at different time intervals. Simultaneous or sequential treatment will depend on the characteristics of the other medicaments used, such as the onset and duration of action 12 200918533 , the level of gold aggregation, clearance rate, etc., and depending on the disease, its stage, and the characteristics of the individual patient. The so-called "pharmaceutically acceptable, meaning that the carrier, diluent or excipient must be with other ingredients of the formulation. Compatible and harmless to its recipients. 5 Dosage. The recommended therapeutic dose is the same as sildenafil: 50 mg, then reduce or increase the dose as appropriate. Pharmacokinetics, pharmacodynamics, and other considerations can change the actual applied agent 1 to a higher or lower value. The dosage of the compound to be administered will depend on the patient's relevant 'age' weight and sex and can be determined by a physician. This dose will preferably be 0.01 mg/kg - 1 mg / kg. The typical daily dose of the active ingredient varies over a wide range and will depend on various factors such as the patient's relevant index, route of administration; age, weight and sex, and can be determined by the physician. In general, the oral and parenteral dosage will be 〇.l-1, 〇〇〇mg/day total active ingredient. The term "therapeutically effective amount" is used herein to treat or prevent an amount of a condition which can be treated by administering a composition of the invention. The amount is sufficient to exhibit detectable therapeuticity, prevention in a group I5 woven system, animal or human. The amount of sexual or ameliorating response. The effect may include, for example, treating or preventing the conditions listed herein. The precise effective amount of the subject will depend on the size and health of the subject, the nature of the condition being treated, and The degree, the recommendation of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the combination of the therapy selected for the administration, or the combination of the two treatments. Therefore, it is useless to specify the effective amount of the shot in advance. A pharmaceutically acceptable salt is one that is suitable for use in contact with humans and lower animal tissues without toxic, irritating, allergic, etc., and which is commensurate with a reasonable benefit/risk ratio within the scope of medical judgment. salt. The pharmaceutically acceptable salt is strong for the job. The compounds of the invention may be prepared in situ when they are finally surface-purified, or may be reacted separately by reacting them with a pharmaceutically acceptable non-toxic domain or acid (including inorganic or organic domains and inorganic or organic acids). To prepare. The term "treatment," as used herein, refers to any treatment of a condition or disease in a mammal, preferably a human, and includes: (1) prevention of a disease or condition in a disease of the disease but not diagnosed with the disease. Occurs in the subject, (2) inhibits the disease or condition, ie prevents its development, (3) reduces the disease or condition, ie causes the condition to subdue' or (4) terminates the symptoms of the disease. The term "medical treatment" is used herein.曰 Including prophylactic, diagnostic, and therapeutic regimens for human or other mammals in vivo or ex vivo. As used herein, the term "subject," refers to a scorpion animal, preferably a mammal, most Humans are preferred, which are articles of treatment, observation or experimentation.

[Finance Mode; J. Detailed Description of Preferred Embodiments Example 1: Analytical Method 15 Unless otherwise stated, the use of Bruker DRX 600: 600 MHz, 13 C · 150 MHz) at 300 K in the indicated solvent for nuclear magnetic resonance Wave "P (H NMR and C NMR, APT). The spectra were determined in deuterated DMS(R) obtained from Cambridge Isotope Laboratories Ltd. The chemical shift (6) is given in ppm from a low magnetic field of tetramethyl oxalate (4). The coupling is usually 20 in J. The peak shape in the NMR spectrum is represented by a symbol, (quadruple peak), 'deduction' (double quadruple peak), 't' (triplet), 'dt' (double triplet), 'd, (double peak) , 'dd' (double doublet), 's' (single peak), 'bs' (wide single peak) and 'm, (multiple peak). The NH and OH signals were set after mixing the sample with a drop of 〇2〇. The melting point was recorded on a Biichi B-545 melting point tester. 200918533 Flash chromatography refers to the purification using the indicated eluent and lycopene (Acros: 0.030-0.075 mm or Merck® 60: 0.040-0.063 mm). The reverse reaction was monitored by thin layer chromatography (TLC) on a ceria coated plastic sheet (Merck precoated silicone 60 F254) using the indicated eluent. Spots were visualized by UV light (254 nm) or 12. Liquid Chromatography-Mass Spectrometry (LC-MS) The LC-MS system consisted of two Perkin Elmer Series 200 micropumps. The pumps were connected to each other via a 50μ1 three-way mixer connected to a Gilson 215 autosampler. The method is as follows: 10 Step total time flow (μΐ/min) A(%) B(%) 0 0 2000 95 5 1 1.8 2000 0 100 2 2.5 2000 0 100 3 2.7 2000 95 5 15 4 3.0 2000 95 5 Α= 100% water with 0.025% HCOOH and 10mmol NH4HCO〇ρΗ= +8

Β = 100% ACN and 0.025% HCOOH Autosampler has a 2μ1 injection loop. The autosampler was connected to a 20-particle Waters Atlantis C18 30x4_6mm column. The branch is at 4 inches. [The Perkin Elmer series 200 column oven is under constant temperature. The column was connected to a Perkin Elmer Series 200 UV meter containing 2.7 μl flowcel. The wavelength is set to 254 nm. The UV meter was connected to a Sciex API 150EX mass spectrometer. The mass spectrometer 15 200918533 has the following parameters: Scanning range: 150-900 amu; Polarity: Positive; Scanning mode: Curve; Resolution Q1: UNIT; Step size: 〇_1〇amu; Time per scan: 0.500 sec; NEB: 10 ; CUR: 10 IS: 5200 ; TEM: 325 ; DF: 30 ; 5 FP: 225 and EP: 10. A light scattering detector is coupled to the Sdex API 150. The light scattering detector is a Sedere Sedex 55 operating at 50 C and 3 bar N2. Control the entire system with G3 powermac. Sildenafil 10 and its N-oxides in mouse plasma and brain samples were analyzed using a universal bioanalytical method including protein precipitation and HPLC with MS/MS detection. Sample preparation. B-guess the protein in the 1 〇〇μ1 blood _, and analyze the 5 μl sample of the obtained solution. The whole brain was homogenized and centrifuged, and a 10 μl supernatant sample was analyzed. Liquid chromatography-series 15 (LC-MS/MS) was performed using a Sciex® 4000 LC-MS/MS. The extracted calibration sample (which was subjected to the same treatment as the study sample) was used to quantify the sample for plasma and brain samples in the range of 丨_5〇〇〇 ng/m^Q 5.0-5000 ng/brain, respectively. Quantify using the peak area of the compound. Fit the calibration curve to the model y = A + Bx + Cx2 (y is the peak area of the analyte, X is the nominal calibration level in ng/ml (plasma) or 20 ng/g (brain)' A is a cut Distance, B is the slope, (: is the description of the curvature). Weighted by 1/χ2. The performance of the LC_MS/MS system is monitored using a reference solution injected at standard intervals. The method used is not verified in detail, so the reported Degree is a good estimate. For blood pooling and brain samples, the lower limit of quantitation (Ll〇q) was established at 1 _00 ng/ml and 5.00 ng/bra, respectively. Using gradient elution by Hypersil 16 200918533 BDS C18 100x4.6mm 3μηι analysis Column, reversed-phase HPLC at a temperature of 45 ° C and a flow rate of 1.00 ml/min : Solvent time (mm) % A %B % c %D 0.00 10.0 40.0 50.0 0.0 1.00 10.0 40.0 50.0 0.0 2.00 10.0 10.0 80.0 0.0 4.00 10.0 10.0 80.0 0.0 4.10 10.0 40.0 50.0 0.0 7.00 10.0 40.0 50.0 0.0 Solvent A lOOmM NH4FA/1%FA Solvent B Milli-Q Water Solvent c Methanol Solvent D Acetonitrile was detected on MS/MS using positive MRM ionization. From 5: Sildenafil N-oxide Sildena Non-Qi 475.3 491.4 Q3 100.1 99.2 10 Example 2: Synthesis of specific compounds 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole [4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sulfonyl]-4-methylpiperazine (sildenafil)' and 17 200918533 as in EP 〇 463 756 Synthesis of indoline _7_oxo-3-propyl-1H-pyrazolo[4,3-♦-midine-5-yl)_4·ethoxy-phenyl] sulphate]-°chen Oxazine (N-dedecyl sildenafil). 1-[[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-.biazolo-5 [4,3_d]pyrimidin-5-yl)-4- Ethoxyphenyl]sulfonyl]-4-methyl-4-oxo-piperazine (sildenafil N-oxide): Dissolve the free domain of sildenafil (1.42 g, 3 mmol) 75 ml of dichlorohydrazine was burned and cooled to -10 °C. The m-chloroperbenzoic acid (m-CPBA, 0.74 g, 3 mmoh 70% in Ηβ) was added to the mixture in small portions, and the solution was stirred at 1:1 10 C for 2.5 hours. Solid k2C03 (2 g) was added and the obtained mixture was stirred (30 mL). %). Mp: > 20 (TC (decomposition). LCMS; Rt: 1.21 min, ([M+H]+ = 491). W-NMR (600 MHz, D6DMSO): (5 15 7.89-7.85 (m , 2H), 7.39 (d, J = 8 Hz, 1H), 4.18 (q, J = 7 Hz, 2H), 4.16 (s, 3H), 3.51-3.43 (m, 4H), 3.04 (s, 3H) , 3.02-2.96 (m, 2H), 2.93-2.88 (m, 2H), 2.78 (t, J = 7 Hz, 2H), 1.77-1.70 (m, 2H), 1.30 (t, J = 7 Hz, 3H ), 0.93 (t, J = 7 Hz, 3H). Example 3: Pharmacological Methods In vitro inhibition of phosphodiesterase was measured at CEREP (128, rue Danton, 92500 Rueil-Malmaison, France) using a widely documented procedure: PDE-I from bovine brain (Nicholson, 1989), PDE-II from human U-937 cells (Torphy '1992) 'PDE-III from human platelets (Weishaar, 1986), from human U937 Nuclear cell pDE-IV (Torphy, 1992), obtained from human blood 18 200918533 small plate PDE-V (Weishaar, 1986) and from the cattle network Membrane pde-VI (Ballard, 1998) The human colon model TIM2 (TNO gut model 2) is a dynamic model of the human large intestine that is analogous to in vivo conditions. It has been artificially digested by many studies (Minekus, 1999). System. Sildenafil N-oxides, and their pharmacologically acceptable salts, are prodrugs. They can be used to treat diseases that can be effectively treated with sildenafil (even with side effects): erectile dysfunction (impotence) And pulmonary hypertension. Example 4: Pharmacokinetics and Pharmacological Test Results 10 Sildenafil and its oxides were administered separately (intravenously (iv) or orally (PO)) to male functional mice (each day) Three animals were interspersed), and thereafter their plasma and two compounds in the brain were analyzed by LC-MS (see above). The data were averaged (n = 3) and collected in the table. 19 200918533 1 : plasma and silicin of sildenafil and its N-oxide sildenafil sildenafil-Ν-oxide plasma brain brain administration time (h) [ng/ml] [ng/g] [ng/ml] [ng/g] Sildenafil 1.0mg/kg iv 0.17 343 125 3.0 0 0.5 14 3 40 2.1 0 1 52 20 0.67 0 3 2.4 1.2 0.61 0 7 0.34 0 0 0 24 0 0 0 0 Sildenafil 10 mg/kg po 0.17 533 155 8.0 0 0.5 457 129 5.3 0 1 260 93 4.0 0 3 32 13 0.48 0 7 5.6 3.1 0.15 0 24 0 0 0 0 Sildenafil-N-oxide 1.0 mg/kg iv 0.17 14 8.6 225 125 0.5 6.1 3.3 49 28 1 8.8 1.8 17 1.8 3 3.9 1.6 0.81 2.7 7 0,31 0 0 0 24 0 0 0 0 Sildenafil-N-oxide 10 mg/kg po 0.17 7.3 5.5 1.6 92 0.5 52 20 1.9 21 1 126 38 2.7 5.5 3 109 η 1.4 2.7 7 47 20 1.1 0.9 24 0 0 0 0 20 200918533 When applied to mice (iv or ρ·〇.) 'sildenafil is minimally metabolized to its bismuth-oxide: its concentration in plasma never exceeds 1-2% of the parent compound, And there is no trace in the brain at all. When the sildenafil-oxime-oxide itself is applied, it is reduced to the parent compound. One hour after sildenafil 5 Oxide Lv_ administration, the concentration of sildenafil in plasma and brain exceeded the concentration of N-oxide. The effect is more pronounced after oral administration: the concentration of sildenafil in plasma and brain is 10-100 times higher than the concentration of bismuth oxide within half an hour after administration of the team oxide. Sildenafil oxide (1 mg) 10 suspended in 1% methylcellulose A was inserted into the chamber (120 ml) of the TIM2 model (see above, Minekus, 1999). Samples were taken from the chamber and dialysate (the latter is a model for the vascular bed of the intestine) at various time intervals and analyzed for sildenafil-N-oxide and sildenafil: Table 2:

V Table 2 Reduction of sildenafil N-telluride in human jiMr靥揲TIM2® Dinafil-you oxygen tow ' :::::·; . . ' i Lion non-cavity dialysate The time of the cavity dialysate (h) [ng/ml] [ng/ml] [ng/ml] [ng/ml] 0 < 1.0 < 1.0 < 1.0 < 1.0 2 6.6 33 11,000 130 ::: ::: 4 4.7 < 1.0 7,800 320 6 4.9 < 1.0 6,400 310 8 6.7 < 1.0 5,500 280 24 2.7 < 1.0 3,300 160 21 200918533 From the above results, it can be seen that 'West within 2 hours after administration That non-N-oxide has been almost quantitatively reduced to sildenafil. Since many studies have confirmed that TIM2 is an in vitro model with high predictive value for gastrointestinal conditions in living humans, it is expected that sildenafil N-oxide will also be reduced to sildenafil after oral administration in humans: it will It is a prodrug. Table 3: Plasma drug binding of sildenafil and its N-oxides. Sildenafil-N-oxide route of administration: IV· pD 1·ν, po #li(mg/ Kg) 1 10 1 10 Cmax (πε/ml) 538.5 (C〇)* 533.3 495.1 (Co)* 2.7 Tniax (hr) 0.0 0.2 0.〇1.0 b (hr) 1.4 1.1 0.4 ---- 5.1 10.8 ' 1 — AUCo^end (ng/ml x hr) 231.6 ___ 661.1 124.9 ""i^""7hrs Tend^j!!_ Tend = 24 hrs . One hand is difficult.24: Tend = 7hrs ^^670.2 ^T^d= 00 ^--- 125.4 _Tend^!!__ 132.9 18.8 Tend — 00 AUC〇-» (ng/ml x hr) .—Note 232.3__ Tend = two clearance rate (mi/nttin/kg) V 〇 (ml/kg) 71.8 ______ 8900.0__ 5000-0 - .-- --- 1.5 - Qin utilization (%) 28.9__ **"*"·--- -------- Yv C — 2.5 ” Brain/plasma ratio 0.4 ___ a 0.3 —--- 〇·, * For i.v_ administration, the Craax value is extrapolated to Τ〇 (time zero). The compounds have different pharmacokinetic properties. 22 200918533 In the small-scale pilot test, 'sildenafil and its N-oxide were administered separately (intravenous (iv) or orally (Ρ·〇·)) to male NMRI mice (3 animals per time point) After that, the presence of N-desmethylsildenafil in their plasma and brain was analyzed by LC_MS (see method above). The data were averaged (η = 5 3) and collected in Table 4. Table 4: Plasma and sputum concentrations of N-desmethylsildenafil--- N-desmethylsildenafil---- Plasma brain '-1 application time (h) [ng/ml] [ng /g] Sildenafil l.Omg/kgi.v. 0.17 6.0 < 1.0 0.5 8.0 < 1.0 Sildenafil 10 mg/kg p.〇. 1 92 15 3 25 4.2 7 30 0 Sildenafil-N - Oxide 1.0 mg/kg iv 0.17 < 1.0 < 1.0 0.5 < 1.0 < 1.0 Sildenafil-N-oxide lOmg/kgp.o. ______ 1 28 < 1.0 3 25 5.1 7 24 8.2 No As expected, when administered to mice (iv or ρ.ο.), sildenafil is metabolized to its N-demethylated analog, a metabolite that also penetrates the blood-brain barrier because it is in the brain. Found in the organization. When sildenafil oxide 23 200918533 was administered, it was also found to be new in the metabolism of N-desmethylsildenafil (observed only after oral administration). To study the activity of sildenafil-N-oxide as an inhibitor of different phosphodiesterases, the compound was tested immediately after sildenafil itself. 5 The results obtained are collected in Table 5. Table 5: Extra-inhibition of phosphodiesterase sildenafil sildenafil-N-oxidase source pICso pIC5〇PDE-I bovine brain 5.0 5.8 PDE-II human U-937 cells <5.0 <5.0 PDE-III human platelets 4.5 < 5.0 PDE-IV human U-937 monocytes 4.8 < 5.0 PDE-V human platelets 7 7 6.7 PDE-VI bovine retina 7.2 6.0 For sildenafil, data collected in Table 5 Those known from the scientific literature were confirmed: this compound is a potent inhibitor of PDE-V and is highly selective for this particular subtype, with the exception of PDE-VI, which is also strongly inhibited. 10 The strength of sildenafil-N-oxide was found to be 10 times lower than that of sildenafil itself and showed considerable selectivity. In summary: when administered orally, sildenafil-N-oxide is filled with the current drug: 24 200918533 匕 Rapidly transferred to the parent compound and converted to desmethylsildenafil, reported, with sildena Non-semi-potential sildenafil metabolites. It has also been found that the sildenafil I oxide itself is not completely inactive: it has about one tenth of the activity of the parent compound. 5 Example 5: Pharmaceutical Formulations For clinical use, sildenafil oxides are formulated into pharmaceutical compositions that are important and new embodiments of the present invention because they comprise the compounds disclosed herein. More specifically, specific compounds. Types of pharmaceutical compositions that may be used include: tablets, (four) tablets, 1 capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), test agents, suspensions, and liquids disclosed herein. Other types that are apparent from the description and common general knowledge in the art will be apparent to those skilled in the art. For example, the active ingredients may also be in the form of inclusion complexes in cyclodextrins, their mysteries or their vinegars. The composition is for oral, intravenous, subcutaneous, intratracheal, bronchial, intranasal, pulmonary, transdermal, frequent film, direct, parenteral or other routes of administration. The pharmaceutical preparation comprises at least sildenafil N-oxide blended with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredient is suitably about Qi% (w/w)-large, 95% (w/w) of the formulation, suitably 〇5%_5〇% (w/w), preferably 20 (w) /w). In some embodiments, the amount of active ingredient is greater than about (w/w) or less than about 0.1% (w/w). The usual method can be carried out by using an auxiliary substance such as a liquid or a solid, a powdery component such as a liquid or solid filler commonly used for medicines, an extender, a solvent, an emulsifier, a lubricant, a fragrance, a colorant and/or a buffer substance. The compound of the invention is made into a dosage form suitable for administration. Commonly used auxiliary substances include magnesium retinate, titanium dioxide, lactose, silk sugar, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk proteins, gelatin, starch, amylopectin, cellulose and derivatives thereof, Animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerin, and disintegrating and lubricating agents such as magnesium stearate, calcium stearate, ten Sodium octa-fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets were prepared using the following ingredients: 10 Ingredients _ 詈 (mg/tablet) Sildenafil N-oxide 10 Microcrystalline cellulose 200 Fumed sulphur dioxide eve 10 Stearic acid 10 15 Total 230 The above group The tablets were mixed and compressed to form tablets each weighing 230 mg. The active ingredient may be premixed with the other 20 inactive ingredients separately prior to mixing to form the formulation. The active ingredients may also be mixed with one another prior to mixing with the inactive ingredients to form a formulation. Soft gelatin capsules may be prepared by capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat or other carrier suitable for soft gelatine capsules. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules may also contain active ingredients as well as solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage unit for rectal administration may be prepared as (1) in the form of a suppository, 5β suppository comprising an active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule comprising vegetable oil, stone oil Or an active substance f mixed with other carriers suitable for gelatin rectal capsules; (d) in the form of a prepared micro-eneus; or (iv) in the form of a dry micro-enema preparation which is reconstituted in a suitable solvent just prior to administration. Composition. The 1 〇 & body preparation can be prepared as a syrup containing the active ingredient and the remainder, _, a concentrated drop or suspension, such as a solution or suspension, for example, by sugar or sugar alcohol and ethanol, water 'glycerol, propylene glycol and A mixture of polyethylene glycols. Such liquid preparations may contain, if desired, coloring agents, flavoring agents, preservatives, saccharin (tetra)methylcellulose or other thickening agents. Liquid preparations can also be in the form of a dry powder which is reconstituted with a suitable solvent prior to use. The solution for parenteral administration can be prepared as a "pharmaceutically acceptable solution for the preparation of the present invention. These solutions can also be used to stabilize the formation of f", preservatives and/or buffering ingredients. The solution of the drug can also be prepared as a dry formulation which is weighted with a suitable solvent prior to use. (1) A formulation or a kit of parts is also provided according to the invention, comprising one of the pharmaceutical compositions of the invention. One or more ingredient containers for the treatment of such a container. Such containers may be accompanied by various written materials, such as the use of a child's moon, or a notice in the form prescribed by the government department 27 200918533, which governs the production, use or sale of the drug product, The notice can reflect the approval of the department for the production, use or sale of a human or veterinary drug. The use of the formulation of the present invention in the manufacture of a medicament for the treatment or demand of a diester acid ester The state of the enzyme, as well as the method of medical treatment, including the application of sildenafil quinone-oxide having a total amount of 5 effects to the treatment, and the requirement to inhibit the phosphodiester The condition of the enzyme or the patient susceptible to the condition. By way of example and without limitation, several pharmaceutical compositions are provided which comprise a preferred active compound for systemic or topical administration. Other compounds of the invention or combinations thereof It may be used in place of (or added to) the compound. The concentration of the active ingredient may vary within the broad ranges discussed herein. The amount and type of ingredients included in the art are well known in the art. To the extent that the following references are useful to those skilled in the art, or to more fully describe the present invention, they are incorporated by reference in their entirety. These documents, or any other documents or citations cited herein, or any references None of the citations are recognized as prior art documents or citations.

Ballard et al (1998) J. Urol. 159: 2164.

Bickel, M.H.,: ''The pharmacology and Biochemistry of 20 N-〇xides", Pharmacol. Reviews. 21(4). 325-355, 1969.

Bundgaard, H. (editor), "'Design of Prodrugs'\ Elsevier, 1985. EP 0 463 756.

Ettmayer, P. et al., Lessons learned from marketed and 28 200918533 investigational prodrugs", J. Med. Chem., 47, 2393-2404, 2004.

Jarvinen, T. et al., "Design and Pharmaceutical applications of prodrugs", pages 733-796 in: S.C. Gad 5 (editor): uDrug Discovery Handbook^, John Wiley & Sons Inc., New Jersey, U.S.A., 2005.

King, F_D., (editor), page 215 in: "Medicinal Chemistry: Principles and Practice", 1994, ISBN 0-85186-494-5.

Minekus, Μ., M. Smeets-Peter, A. Bernalier, S. 10 Marol-Bonnin, R. Havenaar, P. Marteau, M. Alric, G. Fonty, and JHJ Huis in^ Veld. 'A computer-controlled System to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products'. Appl. Microbiol. Biotechnol. 53:108-114, 1999. 15 Nicholson et al. (1989) Brit. J. Pharmacol. : 889-897

Stella, J., "Prodrugs as therapeutics'', Expert Opin. Ther. Patents. 14(3), 277-280, 2004.

Torphy et al. (1992) J Pharamacol Exp Ther 263: 1195-1205. 20 Weishaar et al. (1986) Biochem. Pharmacol. 35: 787-800. [Simple description of the figure 3 (none) [Key component symbol description] (none) 29

Claims (1)

200918533, the scope of application for patent: a 1-[[3-(6,7-dihydro-ι_甲其7 备& LT-7-deutero-3-propyl-1H-pyrazolo} fluorenyl _本基]sulfonyl]-4-methyl_4-oxo bridge-°辰°Qin compound: 2. For example: please (4) the compound of the first item, which is substantially free of H4_ethyl lactyl-3-(6,7-dihydrosuccinemethyl-7-oxo-whenyl-ih mouth than saliva [4,3-d] caid _5_yl) phenyl hydrazino] _4 methyl sulphate or a pharmacologically acceptable salt, hydrate or solvate thereof. 3. A pharmaceutical agent which comprises a compound according to any one of the claims of the patent application, or a pharmacologically acceptable salt, hydrate or solvate thereof. A compound according to any one of the claims of the invention, which is for use in the treatment of erectile dysfunction or pulmonary hypertension. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable lion substance, a pharmacologically active amount of the patent application scope At least one compound of the formula, or a pharmacologically acceptable salt, hydrate or solvate thereof, as an active ingredient. 6. A combination pharmaceutical preparation comprising (1) sildenafil N-oxide or a drug thereof 30 200918533 a physiologically acceptable salt, hydrate or solvate, and (ii) another therapeutic agent for simultaneous Treatment of erectile dysfunction or pulmonary hypertension independently or sequentially. 7. The combination pharmaceutical preparation of claim 6, wherein the other 5 therapeutic agents are sildenafil. 8. Use of a compound according to any one of claims 1-2 for the preparation of a pharmaceutical composition for the treatment of erectile dysfunction or pulmonary hypertension. 9. Use of a sildenafil N-oxide for the manufacture of a medicament for treating erectile dysfunction or pulmonary hypertension in a human or animal patient. A use of a combination preparation of claim 6 for the preparation of a pharmaceutical composition for treating erectile dysfunction or pulmonary hypertension. 15 11. A method for preparing a sildenafil N-oxide, wherein the sildenafil having the formula (1) is oxidized with an oxidizing agent to produce a sildenafil N-oxide having the formula (1A) (1) 12. The method of claim 11, wherein the oxidizing agent is m-31 200918533 chloroperbenzoic acid. 200918533 VII. Designated representative circle: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4