TW200916092A - N-oxides of venlafaxine and O-desmethylvenlafaxine as prodrugs - Google Patents

Abstract

The invention concerns venlafexine-N-oxide and O-desmethylvenlafaxine-N-oxide as prodrugs of venlafexine and its major (active) metabolite O-desmethylvenlafaxine respectively, to pharmaceutical compositions containing these N-oxides, to methods for preparing them, and methods for preparing compositions. The invention relates to N-oxide, having formula (1), wherein R<SP>1</SP> is H or CH3, and tautomers, stereoisomers, hydrates and solvates thereof. The invention also relates to the uses of the N-oxides and compositions, particularly for the manufacture of medicaments useful in the treatment of affections or diseases effectively treatable-albeit with side effects- with venlafexine.

Description

200916092 IX. Description of the invention: [Technical field of 劳^明冷^, the field of invention] H ^ and the field of drugs and organic chemistry, and provided with the general formula (I: 'venlafaxine and 〇_demethyl Record end ~ oxide:

&quot;中星号() privately asymmetric carbon atoms, or, and their j-frames, stereoisomers, hydrates, and solvates, respectively, venlafaxine and its major (active) metabolites A prodrug of methyl venlafaxine and a pharmaceutical composition comprising the compound of S, a method for preparing the compound, and a method for preparing the composition. C Prior Art Background of the Invention Venlafaxine is a phenethylamine bicyclic derivative which is chemically independent of tricyclic, tetracycline or other available anti-repressing agents. Its (_)_ enantiomer is reported to be a more potent inhibitor of norepinephrine synaptosome uptake, while its (+)-enantiomer is more selective in inhibiting 5-tryptamine uptake (H) 〇wen,】994). Venlafaxine is marketed as a racemate. 200916092 CH,

I

/N\ f CH3 OH

0

I ch3 (±) 丨 2_(dimethylamino)-H4-methoxyphenyl)ethyl]·cyclohexanol, venlafaxine (US Patent No. 4,761,501; Pento, 1988) 5 in humans The mechanism of venlafaxine's antidepressant effect is thought to be related to its enhanced neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major metabolite 〇-desmethylvenlafaxine are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Ο-demethyl-venlafaxine is the only major active metabolism 10 substance. Other metabolites are N-demethyl venlafaxine, and hydrazine, quinone-d-desmethylvenlafaxine (Klamerus '1992).琥珀 琥珀 〇 曱 曱 曱 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉 拉This compound is also being developed as a therapeutic agent for vasomotor symptoms associated with menopause. 15 Ν·Oxide has been known since the year of deletion. The present-to-organic oxide is a metabolite of many tertiary amines and, in most cases, an intermediate between tertiary amines and their oxime-dealkylated analogs. Most, but not all, tertiary amine drugs produce strontium-oxide. This is the case, for example, for morphine, propanol, gamma, guilty sniffing and smoking. Ν _ Oxidation occurs from trace amounts to 20 near quantitative conversion changes. - Some N-oxides show more potency than their corresponding tertiary amines 200916092. One of the most famous examples is Librium®, one of the most commonly used drugs in psychiatric and general medicine. However, in more cases τ, helium-oxides were found to be weaker than their corresponding tertiary amines, and Ν-oxidation is most commonly considered to be metabolically inactive. Although it is possible to easily reduce the sense oxygen compounds to their corresponding tertiary amines by chemical means, this occurs to a different extent in the human body. Some rhodium-oxides undergo nearly quantitative reduction conversions to the corresponding tertiary amines and in other cases, the conversion is only a trace amount of reaction, or even completely absent (Bicke L. 1969). Therefore, the formation of oxides and their corresponding tertiary amines is unpredictable. Once formed, the group oxides 10 may be more active, less active or even completely inactive than their corresponding tertiary amines. It is possible to reduce the N-oxide to the corresponding tertiary amine or not. The reaction may be trace only or nearly quantitative when they are available. It has been generally accepted since Paracelsus (‘Sola dosis facit venenum’) 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, the blood $ level is used as an approximation of the concentration of the phase. During drug development, a window of suitable plasma concentration is defined to provide a lower or lower bound of efficacy, and an upper boundary where side effects begin to become apparent. In an ideal situation, it is easy to apply the drug in such a way that the difference between the two is so large that it is effective, but no side effect is caused. In fact, the situation is almost impossible - straightforward, and most drugs show side effects. In most cases, the occurrence of the secondary fairy may be related to the peak gray; the agricultural level is related to the lower limit level of the peak blood concentration super-axis side effects. Venlafaxine produces a peak blood concentration that causes side effects. The most commonly observed adverse events (occurrence rates of 5% or greater), which were associated with the use of venlafaxine and were seen at an equal incidence in 200916092, included persistent hypertension, Headache, weakness, sweating, nausea, constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or unclear vision, and male ejaculation/sexual desire 5 tidal or impotence (Physicians' Desk Reference, 1999; Sinclair, 1998). These adverse effects may significantly limit the dose level, frequency and duration of drug therapy. An extended-release formulation (venlafaxine XR) can be used to attenuate adverse events, but different compounds can also solve the problem. It would therefore be desirable to find a compound that has the advantages of venlafaxine while avoiding its disadvantages. Prodrugs have the same pharmacological properties but have more favorable pharmacokinetic properties. SUMMARY OF THE INVENTION Summary of the Invention When administered orally, venlafaxine-N-oxide and 0-desfenoxalam 15 octyl-N-oxide are filled with current drugs: they are rapidly converted into their parent compounds, respectively. Venlafaxine and 0-desmethyl-venlafaxine. The present invention relates to an N-oxide of the formula (1):

OH

The N-oxide of 200916092 can be substantially free of venlafaxine and demethyl-desmethylvenlafaxine, and their tautomers, stereoisomers, salts, hydrates, and solvates. Venlafaxine oxime-oxide and 0-desmethylvenlafaxine oxime-oxide can be oxidized by using a suitable oxidizing agent, such as m-CPB, venlafaxine or 50-desmethyl venla Fasin to prepare. The present invention relates to racemates, mixtures of diastereomers and individual stereoisomers of the N-oxides of the invention. The invention particularly relates to N-oxides of the formula (1) wherein R1 is CH3. Another preferred embodiment of the invention is a ruthenium-oxide of the formula (1) wherein R1 is ruthenium. Still other preferred embodiments are the (S)- and (R)-enantiomers of the phosphonium-oxide of the formula (1). Venlafaxine-oxime-oxides and compositions comprising the same can be used to treat conditions or diseases that can be effectively treated (even with side effects) with venlafaxine: depression including major depression, generalized anxiety Symptoms, obsessions and behaviors 15 disorders, social anxiety disorders, panic disorder, general depression, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, also known as 'hot flashes. The invention further comprises: a pharmaceutical composition for treating, for example, a disorder or condition treatable by venlafaxine, the composition comprising a bismuth-oxide of formula (1), and a pharmaceutically acceptable carrier: A method of treating a disorder or condition treatable by venlafaxine, the method comprising administering to a mammal in need of such treatment a bismuth-oxide of formula (1); 9 200916092 treating a disorder or condition treatable by venlafaxine a method comprising administering to a mammal in need of such treatment a group oxide of the formula (1); a pharmaceutical composition for treating a disorder or condition treatable by venlafaxine; An N-oxide of formula (1), and a pharmaceutically acceptable carrier; a method of treating a disorder or condition treatable by venlafaxine, the method comprising administering a formula (1) to a patient in need of such treatment N-Oxide; The present invention also provides a ruthenium oxide of the formula (1) for use in the manufacture of a medicament. The invention further relates to a combination therapy wherein a compound of the invention' or a pharmaceutical composition or formulation comprising a compound of the invention is administered simultaneously or sequentially or as a therapeutic agent (or several therapeutic agents) such as venlafaxine or guanidine - Combination administration of demethyl-venlafaxine for the treatment of one or more of the 15 listed conditions. Such other therapeutic agents can be administered simultaneously or after administration of the compound of the invention. The invention also provides compounds, pharmaceutical compositions, kits and methods for treating disorders or conditions treatable by venlafaxine, the method comprising administering a formula (丨) to a patient in need of such treatment N-oxide. The present invention also provides a process for the preparation of the compounds of the present invention and intermediates used in those processes. The compounds of the invention contain asymmetric centers. This will result in two optical isomers. All possible optical isomers and diastereomers (in the form of mixtures and pure or partially purified compounds) are within the scope of the invention. The present invention, 200916092, covers all of these isomeric forms of these compounds. The general formula (1) shows a structure in which the compound has no preferred stereochemistry. The independent synthesis of these diastereomers or their chromatographic separation can be accomplished by suitable modifications to the methods disclosed herein, as is known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline 5 products or crystalline intermediates which are derivatized, if necessary, with reagents containing asymmetric centers of known absolute configuration. The racemic mixture of the compounds can be separated into the individual enantiomers by methods well known in the art, such as coupling a racemic mixture of the compound to the enantiomerically pure 10 compound to form a diastereomeric The mixture of isomers is then separated from the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. It is also possible to separate the racemic mixture of the compound directly by chromatography using a chiral stationary phase: a well-known method in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents having known configurations by methods well known in the art. Some crystal forms of the compound may exist as polymorphs: they are considered to be themselves in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates), or organic solvents commonly used. Such solvates are also within the scope of the invention. Isotopically labeled N-oxides of the formula (1), detectable by PET or SPECT, are also within the scope of the invention. The above also applies to the use of [13C]-, [14C]-, [3H]-, [18F]-, [1251]- or other isotopically enriched atomic markers suitable for receptor binding or generation 11 200916092 The N-oxide of the formula (1). It has been found that the nucleus of venlafaxine and 0-demethyl venlafaxine as a prodrug of their respective parent compound provides the possibility of using these compounds as an alternative, with prolonged persistence Time and attenuate the clinical benefit of peak plasma concentrations, resulting in improved side-effect profiles. Thus, in some embodiments of the invention, a compound of the invention may be provided which is substantially free of the parent compound 1-[2-(didecylamino)-1-(4-methoxyphenyl)ethyl ]-cyclohexanol, venlafaxine, or 〇-desmethylvenlafaxine. 10 By substantially free means that the compound of the invention comprises less than about 50%, 40%, 30%, 20%, 10%, 1%, 0.5% of venlafaxine or 0-demethyl venlafaxine Or venlafaxine or 0-demethyl venlafaxine is not included as an impurity within the detection limit. According to the invention, N-oxides comprising venlafaxine and/or quinone-dehydrazin venlafaxine (substantially free of venlafaxine and/or 150-desmethylvenlafaxine) are contemplated. Pharmaceutical composition. DEFINITIONS As used herein, the term "venlafaxine" refers to the racemic compound (R,S)-l-[2-(dimethylamino)-1-(4-decyloxyphenyl)ethyl] Cyclohexanol. Any compound that is metabolized in vivo to provide a bioactive agent (i.e., a compound of formula (1)) 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. Thus, in the method of treatment of the present invention, the term "administering or administering" should include treating the respective 12 200916092 species with a compound specifically disclosed, or a compound which is not specifically disclosed but which is converted to a specified compound in vivo after administration to a patient. obstacle. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome some of the obstacles encountered in the application of parent drug molecules. These disorders include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism, and targeting limitations (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; 5 2005). Prodrugs, i.e., compounds which are metabolized to the compound of formula (1) when administered to humans by any known route, are within the scope of the invention. In particular, this relates to hydroxyl groups which can be reacted with organic acids to give compounds of the general formula (1) in which additional groups which are readily removable after application are present, for example but not limited to hydrazine, enamine, Manny A base, a hydroxy-methylene derivative 10 derivative, a hydrazine-(decyloxymethylene carbamate) derivative, a carbamate, an ester, a decylamine or a dilute ketone. The term "polymorphism" is defined as the ability of a compound to exist in more than one crystal form (so-called polymorph). Polymorphism is a commonly occurring phenomenon. Polymorphism is affected by several crystallization conditions such as temperature, supersaturation. Level, presence of 15 impurities, solvent polarity, cooling rate effects. Polymorphs can be characterized by several methods such as solid state NMR, solubility testing, DSC or melting point determination, IR or Raman spectroscopy. To provide a more concise description, Some of the quantitative expressions given herein do not use the term "about," limits. It should be understood that whether or not the 20 term "about" is used explicitly, each quantity given herein means the actual value given, and also means an approximation of the value given by such, the approximation may be based on The ordinary art in the art is reasonably derived, including approximations derived from the experimental and/or measurement conditions of such given values. Throughout the description and claims of this specification, the words "including," and variations of the word such as "including 13 200916092 (comprising), and "including (eGmprises), do not exclude other additives, rabbits, whole, Or the intent of the steps. The term "composition," as used herein, encompasses a product comprising a specified ingredient in a predetermined amount or ratio, and the product is obtained directly or indirectly from the specified ingredients in a specified amount. As for the drug site, the term 'this term' encompasses the product of an optional carrier comprising one or more active ingredients and an emotional component, and by combining, complexing or agglomerating any two or more components, or by dissociating - Or a plurality of ingredients, or any product obtained directly or indirectly from the reaction or interaction of the eight or more types of knives, §, the pharmaceutical composition is prepared as follows: the active ingredient is uniformly 10 and closely mixed with the liquid carrier Or a finely divided solid carrier or a combination of the two, and then, if necessary, the product is formed into the desired formulation. The pharmaceutical composition includes sufficient active target compound to produce a desired effect on the course or condition of the disease. Thus, the pharmaceutical composition of the present invention encompasses any composition prepared by blending a compound of the present invention and a pharmaceutically acceptable carrier. In the context of the 'terminology' combination formulation, the context includes both the true combination, ie the N-oxide of the formula (1) physically incorporated in a formulation such as a tablet or injection, and other agents, including Kit iit_〇f_parts), N_oxide of formula (1), and venlafaxine or another agent, in separate dosage forms, and instructions for its use, optionally also for ease of compliance A tool that uses component compounds, such as labels or figures. With a true combination, drug treatments occur simultaneously according to the definition. The contents of the 'package box' can be applied simultaneously or at different time intervals. Simultaneous or sequential treatment will depend on the characteristics of the other agents used, such as the onset and duration of action, plasma levels, clearance rates, etc., as well as on the characteristics of the disease, its stage, and individual patient 14 200916092. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. Dosage: The recommended therapeutic dose is the same as venlafaxine: 75 mg/day, 5 administered in two or three divided doses with the food. Pharmacokinetics, pharmacodynamics, and other considerations may alter the actual administered dose to a higher or lower value. The dosage of the compound to be administered will depend on the relevant indicator, age, weight and sex of the patient and can be determined by a physician. This dose will preferably be from 0.01 mg/kg to 10 mg/kg. The typical sputum dose of the active ingredient varies by a wide range of 10 and will depend on various factors such as the patient's relevant indicators, route of administration, age, weight and sex, and can be determined by a physician. In general, oral and parenteral dosages will range from 0.1 to 1,000 mg per day of total active ingredient. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent that treats or prevents a condition that can be treated by administering a composition of the invention. The amount is the amount of foot 15 to display a detectable therapeutic, prophylactic or ameliorating response in a tissue system, animal or human. This effect can 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 and extent of the condition being treated, the recommendation of the treating physician (researcher, veterinarian, medical doctor or other clinician), and 20 The selected treatment, or combination of treatments, is administered. Therefore, it is useless to specify an exact and effective setting in advance. The term "treating" as used herein refers to any treatment of the condition or disease of a mammal, preferably a human, and includes: (1) prevention of a disease or condition in a subject susceptible to the disease but not diagnosed with the disease Occur, (2) 15 200916092 Suppressing a disease or condition, ie preventing its development, (3) mitigating a disease or condition, ie causing the condition to subside, or (4) terminating the symptoms of the disease. As used herein, the term "medical table therapy" is intended to include prophylactic, diagnostic, and therapeutic regimens for human or other mammals in vivo or ex vivo. As used herein, the term "subject" as used refers to an animal, preferably a mammal, most preferably a human, which is the target of treatment, observation or experiment. [Embodiment J Example 1: Analytical method unless otherwise Nuclear magnetic resonance spectroscopy (丨H NMR and 13C isfMR, ΑΡΤ) was determined in the indicated solvents using a Bruker DRX 600: 600 MHz, 10 13c . 150 MHz) at 30 〇 κ.

Spectra were determined in deuterated DMSO obtained from Laboratories Ltd. The chemical shift is given in ppm from a low magnetic field of tetramethyl decane (4). Give the coupling constant J along the edge. The peak shape in the NMR spectrum uses the symbols 'q, (quadruple peak), 'dq, (double quadruple 15 peak), ' triplet peak', 'dt' (double triplet), 'd, (double peak) , Md, (double doublet), 's' (single peak), 'bs' (wide single peak) and 'm, (multiple peak). The NH and OH signals were identified after mixing the sample with a drop of D2. Melting points were recorded on a Btichi B-545 melting point tester. Flash chromatography refers to the purification using the indicated eluent and lycopene (Acros: 2 〇 0.030-0.075 mm or Merck yoke 60: 0.040-0.063 mm). The reaction was monitored by thin layer chromatography (TLC) on a ceria coated plastic sheet (Merck precoated silicone 60 F254) using the indicated eluent. The dots were visualized by UV light (254 nm) or 12. A system consisting of two Perkin Elmer series 歹 ij 200 micropumps was used for liquid chromatography-mass spectrometry (LC-MS). The pumps are connected to each other via a 50 μl three-way mixer connected to a Gilson 215 automatic sampler. The method is as follows: Step Total time Flow rate (μΙ/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 4 3.0 2000 95 5

5 Α=100% water with 0.025% HCOOH and 10 mmol NH4HCOO ΡΗ= +/_3 B=100% ACN and 0.025% HCOOH 戎The automatic sampler has a 2 μΐ injection loop. The autosampler was connected to a Waters Atlantis Cl8 30x4.6 mm column containing 3 μm particles. The column was thermostated in a Perkin Elmer Series 200 column oven at 4 〇 10 °C. The column was coupled to a Perkin Elmer Series 200 UV meter containing 2.7 μΐ flowcel. The wavelength is set to 254 nm. The UV meter was connected to a Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: Scan range: 150-900 amu; Polarity: Positive; Scan mode: Curve 15 line 'resolution Q1: UNIT; Step size: 〇_1〇a ni.u.; Time of each scan : 0.500 sec; NEB: 10 ; CUR: 10 is: 5200 ; 1ΈΜ: 325 ; DF: 3〇; FP_225 and EP: 10. Connect the light scattering detector to the sciex api i5〇. Light Moonlight 4 is a test of Sedere Sedex 55 operating at 50 C and 3 bar N2. Control the entire system with G3 powermac. 17 200916092 Venlafaxine 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. The protein in 100 μM of plasma was precipitated with acetonitrile, and a 5 μΐ sample of the obtained solution was analyzed. The intact brain was homogenized and centrifuged, and the supernatant was analyzed. Liquid chromatography-serch chromatography (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 ^000 ng/ml*10 5 ·〇-5〇〇〇 ng/brain, respectively. The peak area of the compound is used to quantify. 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 (blood) or ng/g (brain), A is cut Distance, B is the slope, and C is the description of the curvature). Weighted with ι/χ2. The performance of the LC-MS/MS system was monitored using a reference solution injected at a quasi-interval. No. 15 has verified this method in detail, so the reported concentration is a good estimate. For plasma and brain samples, the lower limit of quantitation (LLOQ) was established at 1.00 ng/mi and 5.00 ng/brain, respectively. A value less than ll 〇 q is given as the best estimate. Reversed-phase HPLC was performed on a Hypersii BDS C18 100 x 4.6 mm 3 μιη analytical column using a gradient elution at 45 C and a flow rate of 1.00 ml/min: 20 18 200916092 Solvent time (min) % A %B %c %D 0.00 10.0 70.0 0.0 20.0 1.00 10.0 70.0 0.0 20.0 2.00 10.0 10.0 0.0 80.0 4.00 10.0 10.0 0.0 80.0 4.10 10.0 70.0 0.0 20.0 7.00 10.0 0.0 0.0 20.0 Solvent A 100 mM NH4FA/I% FA Solvent B Milli-Q Water Solvent c Solvent Solvent D Acetonitrile was detected on MS/MS using positive MRM ionization. Measured ion

0 · 疋· Venlafaxine Q1 278.3 Q3 121.1 Venlafaxine-N-oxide 294.5 121.1 10 Example 2: Synthesis of specific compounds Synthesis (R, S)-l-[2 as described in EP 1 721 889 -(didecylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol (venlafaxine) and (R,S)-l-[2-(dimethylamino) 1-(4-Hydroxyphenyl)ethyl]-cyclohexanol (0-desmethylvenlafaxine). The latter alternative is as follows. 19 200916092 (R,S)_l-[2-Oxo-(dimethylamino)-1-(4-decyloxyphenyl)ethyl]-cyclohexanol (venlafaxine N-oxide) : Venlafaxine (0.28 g, 1.02 mmol) was dissolved in 20 ml DCM and cooled to -10 °C. To the reaction mixture was added m-chloroperbenzoic acid 5 (m_CPBA' 0.8 g, 2.02 mmol) and the solution was stirred at -10 ° C for 30 min. Solid K2C03 (2 g) was added and the resulting mixture was stirred at (TC) for 30 min. The reaction mixture was filtered (glass funnel) and carefully washed with DCM. The obtained solution was concentrated and passed through flash chromatography (Si 〇 2, DCM / MeOH (95/5 followed by 9/1)) EtOAc (EtOAc: EtOAc (EtOAc) + = 294). 'H-NMR (600 MHz, D6DMSO): 5 7.12 (bd, J = 8 Hz, 2H), 6.86 (bd, J = 8 Hz, 2H), 3.95-3.89 (m, 1H), 3.73 (s, 3H), 3.56-3.52 (m, 1H), 3.28-3.25 (m, 1H), 3.14 (s, 3H), 2.95 (S, 3H), 1.69-1.53 (m, 3H), 1.47- 1.42 (m, 1H), 15 1.38-1.32 (m, 2H), 1.3M.25 (m, 1H), 1.02 (dt, J = 11 Hz, 4

Hz, 1H), 0.87 (dt, J = u Hz, 4 Hz, 1H), 0.77.0 69 (m, 1H). Oxygen bridge _(dimethylamino) small (4-pyridyl)ethyl]-cyclohexanol (〇-desmethylvenlafaxine N-oxide) can be prepared by the same method. 20 (S)- and (R)-enantiomers of venlafaxine were synthesized as described in the scheme below, and their respective N-oxide and oxime-dehydrazino analogs. 20 200916092

LAH

Split

21 200916092

OMe (S)-venlafaxate oxide

0 Me (S)-venlafaxine

OMe (R)-venlafaxine

OMe (R)-venlafaxate oxide

〇-desmethyl (S)-venlafaxine

〇-demethyl (s&gt;-Wenla 1#; octyl oxide

Me2N

〇-desmethyl-(R)-venlafaxine

〇 HO. Me2N

Ο-demethyl... (R)·venlafaxine oxide m,S)-l-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)-cyclohexane Alcohol (venlafaxine, 1〇) ·· Dissolve cyclohexanol (33g, 0.13 mol) in decanoic acid (99%, 54 mL, 1.43 mol) by adding furfural (37%, 41 mL, 1.48 mol) And water (33〇mL) 10 in. The mixture was refluxed for 2 h. The reaction mixture was concentrated to 15 () EtOAc (1), EtOAc (EtOAc) (EtOAc) The aqueous layer was cooled in an ice bath and verified to pH ~1 通过 by the addition of 50% Na. The mixture was extracted with ethyl acetate (3×100 mL), dried over Na.sub. Yield: This material (23.8 g, mainly compound 11) was suspended in diethyl ether (5 mL) and treated with hydrogenated aluminum (3.8 g, 0.1 mol). The suspension was stirred at room temperature for 18 h. 5 N KOH (16 mL) was carefully added and the mixture was stirred for 15 min. The solid was removed by filtration on celite and washed (diethyl ether, 300 mL). The filtrate was dried (sodium sulfate) and concentrated. Yield: 21.4 g of compound 10 (60%) as a white solid. 22 15 200916092 'H-NMR (300 MHz, CDC13): (5 7.05 (d, 2H, J = 8.8 Hz), 6-81 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 3.27 (t, 1H, J = 12.6), 2-93 (dd, 1H, 2J = 3.2 Hz, 3J = 12.5 Hz), 2.32 (s, 6H), 2.3〇 (dd, 1H, 2J = 3.2 Hz, 3J 12.5 Hz), 1.82-1.61 (m, 3H), 5 L60-1·# (m, 3H), 1.42-1.22 (m, 2H), 1.01-0.78 (m, 2H). R-venlafaxine (top Compound 2) in the scheme: (R,S)-venlafaxine (23.4 g, 84 mmol) was dissolved in ethyl acetate (160 mL). To this solution was added 〇-dimethylphenyl tartaric acid (18 7 g) , 48 mm is called a solution in ethyl acetate (130 mL). The salt began to precipitate within 10 min.

10 The mixture was stirred for 4 hours at the temperature. The precipitate was collected by tear on a glass screening procedure and washed with ethyl acetate (2×100 mL). White crystalline solid. The solid was recrystallized from ethyl acetate:methanol (6:1, 100 mL). The solid was collected on a glass screening program. Yield: 14. g. The material was treated with 2N NaOH (cold, 180 mL). The aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phase was washed with 2 N NaOH 15 (cold '75 mL) then with water until the washings were neutral (pH 7). The organic phase was dried (sodium sulfate) and concentrated. Yield: 8.1 g of R-venlafaxine (2) as a white crystalline solid. M.p.: 106 ° C - l 〇 9_5t. [a] D23 = -8.0 (c = 1.5, MeOH). Chiral HPLC: 99% e_e·i-NMR (CDC13): See above. 20 s-venlafaxine (1): The mother liquor of the split (see above) was released by washing with 1 N NaOH (4 x 100 mL), water (3 x 200 mL) and brine (100 mL). The organic phase was dried (sodium sulfate) and concentrated. The oil is quickly consolidated. This material was redissolved in ethyl acetate (75 mL). Add L-xylylene tartaric acid (11.3 g, 29 mmol) 23 200916092

A solution in ethyl acetate (75 mL). Precipitation started within 5 minutes. Ethyl acetate (50 mL) was added and the mixture was stirred at room temperature for 72 hr. The solid was collected on a glass filter. Yield: 14 2g. The material was treated with 2NNa〇H (cold, UOmL). The aqueous phase was extracted with ethyl acetate (3×2 〇〇 mL). The organic phase was washed with 2 N NaOH 5 (cold, 75 mL) then with water until the washings were neutral (pH 7). The organic phase was dried (sodium sulfate) and concentrated. Produced: 6 7 § S-venlafaxine (1) as a white crystalline solid. Mp 1〇4_5. 〇1〇6. (:[α]〇23 = + 13.Mc = 1.6, MeOH). Chiral HPLC: 98% e.e. 1h_nmr (cdci3): see above. 10 s-venlafaxine N-oxide (3) The crude material (2.2 g, 7.5 mmol) has been obtained by FAI (1〇6796) according to the procedure described for 4. Pure 3 was obtained by column chromatography (gradient dichloromethane: methanol &lt;RTI ID=0.0&gt;&gt; Yield: 1.70 g (5.8 mmo, 78%) of 3 as a yellowish solid. [α]〇23 15 =-20.8 (C = io, MeOH) = ^-NMR (300 MHz, CDC13): 5 7-〇9 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 4.16 (m, 1H), 3.79 (s, 3H), 3.51 (dd, 1H, 2J = 3.8 Hz, 3J = 12.7 Hz), 3·41 (m, 1H), 3.27 (s, 3H ), 3.07 (s, 3H), 1.78-1.60 (m, 3H), 160-1.35 (m, 4H), 1.29-1.01 (m, 2H), 0.95-0.76 (m, 1H). 20 R-venlafaxine N-oxide (4) R-venlafaxine (2, 1.0 g, 3.4 mmol) was dissolved in dichloromethane (60 mL). The solution was cooled to _i 〇 °c. Add m-CPBA (fresh, 2.9 g, 7.3 mm 〇l). The suspension was stirred at -UTC for 30 min. TLC detection reveals full meta-transformation. Add K2C〇3 (5·〇 g, 36 mmol) and mix the mixture at 〇°c for 24 min. Dichlorosilane (50 mL) was added and the suspension was filtered. The mash was dried and concentrated. The crude product was purified as above. Produced: g (3.0 mmo, 90%) of a white solid. [α] 〇 23 : Not determined. 1H-NMR (300 MHz, CDC13): see above. 5 〇-desmethyl-S-venlafaxine (5) A solution of diphenylphosphine (18 mL, 0.1 mol) in dry tetrahydrofuran (120 mL) was cooled to &lt;1&quot; Add n_BuLi (25 μm, 50 mL in hexane) and additional tetrahydrofuran (4 〇 mL). The mixture was stirred at -10 ° C for 30 min and then allowed to warm to 〇 ° c. At this temperature, a solution of snorla 10 fasin, 6.2 g, 23 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred for 2 hours while allowing the temperature to rise to room temperature and then maintained at reflux temperature for 16 hours. The reaction mixture was cooled to room temperature, poured into 2N EtOAc (EtOAc, EtOAc) The aqueous phase was washed (3 x 300 mL of acetic acid) and then neutralized (pH 7) with the aid of slow (丨) addition of NaHC〇3 and extracted (ethyl acetate &apos; 6 x 300 mL). The organic phase was dried (NajO4) and concentrated in vacuo. The residue was suspended in ethyl acetate (100 mL) and stirred for 3 min. The solid was collected on a glass filter and washed with ethyl acetate until the odor of monophenylphosphine was no longer detected. White solid. Yield: 4.6 g (17.5 mmol, 76%). 20 m.p. 237.3t-237.9°C. [a]D23 = +17.0 (c = 〇·88, Me〇H). 'H-NMR (300 MHz, DMSO-d6): 5 9.12 (br, 1H), 6.94 (d, 2H, J = 8.3 Hz), 6.62 (d, 2H, J = 8.3 Hz), 5.37 (br, 1H) ), 2.98 (m, 1H), 2.71 (t, 1H, J = 5.8 Hz), 2.34 (m, 1H), 2.14 (s, 6H), 1.64-1.22 (m, 7H), 1.20-0.78 (m, 3H). 25 200916092 0-Demethyl-R-venlafaxine (6) As above, starting from R-venlafaxine (5.0 g, 18 mmol), using diphenyl in hexidine (2.5 Μ, 41 mL) Phosphine (14 mL) and n-BuLi. Yield: 3.8 g (14.5 mmol, 80%). Mp 235.5 ° C-237·Γ (3. [a ]d23 = -21.3 (c = 5 0.9, MeOH). H-NMR (300 MHz, DMSO-d6): see above. O-desmethyl-S- Venlafaxine N-oxide (7) Ο-desmethyl-S-venlafaxine (5,1·5 g, 5.7 mmol) was suspended in di-methane (100 mL). Cool to -l 〇 ° C. Add m-CPBA (4.8 g, 12 mmol). Stir the suspension for 60 min at -l 〇 °c. TLC assay 10 reveals complete conversion. Add K2C03 (7.5 g, 54 mmol) The mixture was stirred for 30 min at 0 ° C. Methylene chloride (100 mL) was added and the suspension was filtered. The residue was stirred in methanol (300 mL) and filtered again. Solution (yield: 7.1 g). Purify the material by column chromatography: dissolve the crude product in methanol (2 〇 15 mL) and add to the column (c. (200 mL) followed by elution with dichloromethane: 7]VI in NH3, 1:1 in methanol. Yield: 1.15 g (4.1 mmol, 72%) of compound 7 as a pale yellow solid. [a]D23 = -26_8 (c = 0.8, MeOH). 'H-NMR (300 MHz, DMSO-d6): (5 9.66 (br, 1H), 6.98 (d, 2H, J = 8.3 Hz), 6 .69 (d, 2H, J = 8.3 2〇Hz), 3.88 (m, 1H), 3.55 (dd, 2J = 2.4 Hz, 3J = 12.7 Hz, 1H), 3.34 (br, 1H), 3.20 (dd, 2J = 2.4 Hz, 3J = 12.7 Hz, 1H), 3.14 (s, 3H), 2.95 (s, 3H), 1.69-1.20 (m, 6H), 1.11-0.66 (m, 4H). 0-desmethyl -R-venlafaxine N-oxide (8) as above - Ο Ο - demethyl _r_venlafaxine (6, 1.5 g ' 5.7 mmol) 26 200916092 start. Produced: 1.20 g (4.3 mmo b 75% ) yellowish solid. [a] D23 = + 16.3 (c = 0.8, MeOH). W-NMR (300 MHz, DMSO-d6): see above. Example 3: Pharmacological Method 5 by CEREP (128, rue Danton) , 92500 Rueil-Malmaison, France) or in Solvay Pharmaceuticals BV (CJ van Houtenlaan 36 ' 1381 CP Weesp 'Netherlands) used in a widely documented program to obtain the in vitro affinity of the neurotransmitter reuptake site. The affinities for serotonin (Tatsumi ' 1999), norepinephrine (pach〇l CZyk, 1991) and dopa 10 amine reuptake site (Pristupa, 1994) were measured. In vitro functional inhibition of [3H]-5-hydroxytryptamine reuptake: Male rats (Wistar Hsd/Cpb: WU; 175-200 g) were decapitated, the cerebral hemispheres were rapidly removed, and the P2-synaptosome fraction was prepared. Synaptosomes were pre-incubated for 15 min at 37 ° C in a medium containing the MAO inhibitor Pagilin (7 μM) in the absence or presence of the test compound. Subsequently, the synaptosome was exposed to [3Η]-5-hydroxy hydroxy female (〇.2 mM final concentration) for 1 〇 min. The [H] serotonin uptake was terminated by filtration with a collector and unbound radioactive material was removed by extensive washing. Filter plates with synaptosomes were dried and the amount of serotonin present was determined by Betaplate liquid scintillation counting. The inhibitory effect on [3h]_5-hydroxytryptamine was expressed as a ρΙ(:5 value, which is the maximum inhibition of the radiolabeled neurotransmitter uptake - the negative logarithm of the concentration at half time. PIC5 〇 疋 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 平均值 PIC PIC PIC PIC PIC PIC PIC The experimental details are as follows: 27 200916092 (Coyle, 1969). [H]-In vitro functional inhibition of norepinephrine reuptake: Male rats (WiStar Hsd/Cpb: WU · ' 175_200 phantom decapitation, rapidly removed The hypothalamus, and the crude synaptosome fraction was prepared. The synaptosome was pre-incubated in the medium containing the MAO inhibitor Paglin (7 μM) in the absence or presence of the test compound at 37 ° C. Subsequently, The synaptosome was exposed to [3Η]_de-adrenalin (0.4 mM final concentration) l5mip to stop [3H]-de-adrenergic uptake by filtration with a collector and to remove unbound radioactive material by sufficient washing. Drying Filter plate with synaptosome' and through Betaplate solution The amount of [3h]-norepinephrine present was determined by 10-body scintillation counting. The inhibitory effect on the uptake of [3h]_norepinephrine was expressed as a value which is the maximum inhibition of radiolabeled neurotransmitter uptake. The negative logarithm of the concentration at half. The pICso value given is the average of 2-9 experiments performed in duplicate. The test compound (ΙΟ-2Μ, dissolved in DMSO) was diluted in Krebs Ringer I5 buffer to reach ΙΟ- Test concentrations of 8 to ΙΟ·5 。. Further experimental details are as described (Coyle, 1969). In vitro functional inhibition of [3H]-dopamine reuptake: male rats (Wistar Hsd/Cpb: WU; 175-200) g) decapitation; rapid removal of the striatum; and preparation of the crude synaptosome fraction (P2) by homogenization and centrifugation. Monoamine oxidase inhibitor at 37 ° C in the absence or presence of test compound Synaptic bodies were preincubated in pajlin (7xl〇·6 M) for 15 min (Coyle ' 1969). Subsequently, [3h]-dopamine (2x1〇_7M final concentration) was added and incubation continued for 10 min. [3H]-Dopamine uptake and washing with discate buffered saline The contact was measured four times. The amount of _dopamine in the synaptosome was determined by Betaplate liquid scintillation meter 28 200916092. (d) Test compound in the range of 9 μ·5 degrees. Using PIC遽 (drug caused by 5〇%: negative concentration at the time of effect) Logarithm) indicates the inhibition of the intake of p-dopamine. - Inhibition of DA uptake in duplicate. The human colon model ΤΙΜ2 (salectal model 2) is an analogy of the human body condition of the large intestine. It is an artificial digestive system that has been confirmed by many studies (test, 1999). a Venlafaxine-N-oxide is a prodrug of the parent compound. They can be used to treat diseases that can be effectively treated with venlafaxine (even with side effects): depression, including generalized depression, generalized anxiety, obsessive-compulsive and behavioral disorders, social anxiety, panic Symptoms, general depression, diabetic neuropathy, migraine, and vasomotor symptoms associated with menopause, also known as 'hot tide'. Example 4: Pharmacokinetics and Dimensional Test Results Venlafaxine and its N-oxides, respectively formulated in 40% HPPCD or 1% methylcellulose, were administered separately (intravenous (iv·) or orally (po) )) Male NMRI mice (3 animals per time point), after which their plasma and brain two compounds were analyzed by LC-MS (see method above). The data were averaged (n = 3) and collected in Table 1. 29 200916092 Table 1: Plasma and brain concentrations of venlafaxine and its N-oxides Venlafaxine venlafaxine-N-oxide plasma brain time (h) [ng/ml] [ Ng/g] [ng/ml] [ng/g] Venlafaxine 1.0mg/kg iv 0.17 250 710 0.32 0.19 0.5 97 289 0.12 0 1 49 200 0.10 0 3 4.7 15 0 0 7 0.30 1.7 0 0 24 0.37 0 0 0 Venlafaxine 10mg/kgp.o. 0.17 630 1133 2.5 0 0.5 543 2267 7.0 0.37 1 523 1800 3.0 0.09 3 38 137 0.31 0 7 3.6 15 0.06 0 24 0 0 0 0 Venlafaxine-N- Oxide 1.0 mg/kg iv 0.17 42 56 623 3.3 0.5 22 52 173 58 1 8.0 26 39 8.1 3 0.59 3.0 7.3 0.44 7 0 0.85 0.16 0.15 24 0 0 0 0 Venlafaxine-N-vapor 10 mg/kgp. o. 0.17 82 55 1040 14 0.5 72 167 840 33 1 117 353 183 6.7 3 77 280 38 1.8 7 3.3 12 0.75 1.6 24 0.63 0 0.12 0 30 200916092 In mice, venlafaxine is only minimally metabolized into its N-oxide: its concentration in plasma never exceeds 1-2% of the parent compound, and only trace amounts can be found in the brain. When venlafaxine-N-oxide is applied itself, it is reduced to the parent compound. About one hour after the application of i.v. 5 of venlafaxine_N-oxide, the concentration of venlafaxine in plasma and brain exceeded the concentration of N-oxide. The effect is more pronounced after oral administration. · The concentration of rafaxine in plasma and brain rises to a level 1 〇_1 〇 0 times higher than the concentration of N-oxide. Will be suspended at 1 ° /. The venlafaxine_N_oxide (丨mg) 10 in the cellulose was inserted into the chamber (12 〇 ml) of the ΉΜ2 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 different time intervals and analyzed for venlafaxine_N_oxide and venlafaxine: Table 2: --^ g^j^N- 夸 在 in the human colon model TIM2 ^ 痗 痗 ----- : : Venlafaxine oxide venlafax ------ dialysate cavity - 1 dialysate time ( h) [ng/ml] [ng/ml] [ng/ml] [ng/ml] 0 &lt; 1.0 &lt; 1.0 &lt; 1.0 &lt; 1.0 2 2.0 7.4 5,400 320 4 2.0 1.2 4,700 470 6 2.0 1.0 4,600 430 8 1.9 &lt; 1.0 3,900 370 24 &lt; 1.0 &lt; 1.0 210 ------- 31 200916092 From the above results, it can be seen that venlafaxine N-oxide has been almost quantified within 2 hours after administration. Restored to venlafaxine. 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 venlafaxine N-oxide will also be reduced to venlafaxine after oral administration in humans: it will be Prodrug. Table 3: Plasma pharmacokinetics of venlafaxine and its N-oxides Venlafaxine venlafaxine-N-oxide route of administration: ivpoivpo dose (mg/kg) 1 10 1 10 Cmax (ng/ Ml) 407.9 (C〇)* 630.0 1205.2 (C〇)* 1040.0 Tmax(hr) 0.0 0.2 0.0 0.2 U (hr) 0.8 0.9 0.8 3.1 AUC〇-end (ng/ml x hr) 194.3 943.4 361.6 841.6 —Note Tend = 24 hrs Tend = 7 hrs Tend = 7 hrs Tend = 24 hrs AUC〇-〇〇(ng/ml x hr) 194.8 948.0 361.7 842.2 One note 萚Tend= 00 Tend = 00 Tend = 00 Tend = 00 Clearance rate (ml /min/kg) 85.6 - 46.1 - VD (ml/kg) 6200.0 - 3000.0 - Bioavailability (%) 48.7 - 23.3 - Brain/plasma ratio 3.1 3.4 0.1 0.0 * For iv administration, extrapolate the C value to Τ〇 (time zero) 32 200916092 It can be seen from the data given above that the volume and bioavailability of venlafab is better than that. More obviously than those of hunger oxides, this _ compound „不—药(四) mechanics money. The poor materials given by silk ι can also be seen that 'venlafaxine good oxides hardly penetrate the brain: therefore, significantly different Brain/plasma ratio. Demethylating, itching team 14 and secret 槿艚 _

33 200916092 The in vitro pharmacology data listed in the above table clearly shows that venlafaxine is the most potent inhibitor of 5-tryptamine reuptake. The (8)- and (5)-enantiomers showed only minimal differences. The major metabolite 〇-norvine venlafaxine was found to be equivalent to venlafaxine, both as a racemate and in its 5 individual enantiomer form. The N-oxides of venlafaxine and oxime-demethyl-venlafaxine (as racemates as well as the individual (R)- or (S)-enantiomers) were found to be virtually inactive. Example 5: Pharmaceutical Formulations For clinical applications, N-oxides of formula (1) are formulated into pharmaceutical compositions 10, which are important and novel embodiments of the invention, as they comprise the disclosures disclosed herein The compound 'more specifically' is a specific compound. 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 as disclosed herein, or in the art Other types apparent from the description of the specification and common general knowledge, such as the 'active ingredient', may also be in the form of inclusion complexes in cyclodextrins, their ethers or their esters. The composition is for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other routes of administration. The pharmaceutical preparation comprises at least one salt of the formula (1) admixed with at least one pharmaceutically acceptable adjuvant, eliminator and/or carrier. • The total amount of the tongue component is suitably from about 〇l% (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w), preferably from 1% to 25%. (W/W). In one embodiment, the amount of active ingredient is greater than about 95% (w/w) or less than about 〇l% (w/w). 34 200916092 by conventional means, using auxiliary substances such as liquid or solid, powdered Ingredients such as pharmaceutically acceptable liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, perfumes, colorants and/or buffer materials can be formulated into a dosage form suitable for administration. Commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, Yan sugar, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, starch, branched chain powder, cellulose and their derivatives. , 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 glycerol, and disintegrating and lubricating agents such as magnesium stearate, calcium stearate , octadecyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets were prepared using the following ingredients: Ingredients _ 詈 (mg / tablet 齑Π venlafaxine N - oxide 10 15 microcrystalline cellulose 200 fumed) SiO 10 碣 10 碣 10 20 20 20 20 The components are combined and compressed to form tablets each weighing 230 mg. The active ingredient may be pre-mixed with other inactive ingredients separately before being mixed to form a preparation. The active ingredient may also be active before being mixed with the inactive ingredients to form a preparation. The ingredients are mixed with each other. 35 200916092 Soft gelatin capsules may be prepared in capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat or other carrier suitable for soft gelatine capsules. Hard gelatine capsules may contain granules of the active ingredient. It may contain the active ingredient as well as solid powdery ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may Prepared as (i) in the form of a suppository, the suppository comprising an active substance mixed with a neutral fat base; (ii) a gelatin rectum In the form of a capsule comprising an active substance in admixture with vegetable oil, paraffin oil or other carrier suitable for gelatin 10 rectal capsules; (iii) in the form of a prepared micro-enema; or (iv) in the form of a dry micro-enema preparation, The formulation is to be reconstituted in a suitable solvent just prior to administration. The liquid formulation can be prepared as a syrup, a brew, a concentrated drop or suspension containing the active ingredient and the remainder, for example, in the form of a solution or suspension, Part of, for example, consisting of a mixture of sugar or sugar alcohol and ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin and Weimethylcellulose or others. The thickening agent may also be prepared in the form of a dry powder which is reconstituted with a suitable solvent prior to use. A solution for parenteral administration may be prepared as a solution of the formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain a stabilizing ingredient, a preservative and/or a buffering ingredient. Solutions for parenteral administration may also be prepared as A dry formulation which is reconstituted with a suitable solvent prior to use. According to the invention there is also provided a formulation and a 'package kit" comprising a 36 200916092 or a plurality of containers containing one or more of the pharmaceutical compositions of the invention, For medical treatment. Such a container may be accompanied by various written materials, such as instructions for use, or a notice in the form prescribed by a government agency governing the production, use or sale of a pharmaceutical product, the notice reflecting the department for the person 5 Or the approval of the production, application or marketing department of veterinary drug delivery. The use of the formulation of the invention in the manufacture of a medicament for the treatment of depression, including major depression, generalized anxiety disorder, obsessive-compulsive and behavioral disorders, social Anxiety disorders, panic disorder, general depression, diabetic neuropathy, migraine, and vasomotor symptoms associated with menopause, also known as 'hot tides', and at least 10 methods of treatment or treatment An N-oxide of the formula (1) is administered by itself or, in the case of a prodrug, to the following diseases After: Depression including major depression, generalized anxiety disorder, obsessive-compulsive and behavioral disorders, social anxiety disorder, panic disorder, general depression, diabetic neuropathy, migraine and vasomotor related to menopause 15 symptoms, also known as 'hot tide'. By way of example and not limitation, several pharmaceutical compositions are presented which comprise a preferred active compound for systemic or topical administration. Other compounds of the invention or combinations thereof may be used in place of (or in addition to) the compound. The concentration of the active ingredient can vary within the broad range 20 discussed herein. The amount and type of ingredients that can be included are well known in the art. References In order to achieve the degree of use of the following references to those skilled in the art, or to more fully describe the present invention, they are incorporated herein by reference. None of these documents, or any other literature or citations cited herein, or citations of any of the references cited in the Japanese Patent Application No. 37 200916092, is hereby incorporated by reference.

Bickel, MH,: &quot;'The pharmacology and Biochemistry of N-oxides", Pharmacol. Reviews. 21(4), 325-355, 1969. 5 Bundgaard, H. (editor), &quot;Design of Prodrugs,\ Elsevier , 1985.

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Jarvinen, T. et al., "Design and Pharmaceutical applications of prodrugs", pages 733-796 in: SC Gad (editor): ''Drug Discovery Handbook&quot;, John Wiley &amp; Sons Inc., New Jersey, USA, 2005 20 King, FD, (editor), page 215 in: "Medicinal Chemistry:

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Marol-Bonnin, R. Havenaar, P. Marteau, M. Alric, G. Fonty, and JHJ Huis in^ Veld. &quot;A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of Fermentation 5 products'. App\. Microbiol. Biotechnol. 53:108-114, 1999.

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Tatsumi, M., et al., Eur. J. Pharmacol., 368, 277-283, 1999 Patent and Patent Application EP 1 721 889 US 4,761,501 2〇 [Simple Description] (None) [Key Symbol Description] (none) 39

Claims (1)

200916092 X. Patent application scope: L—N-oxides having the general formula (1) and their tautomers, stereoisomers, hydrates and solvates: The asterisk (*) marks an asymmetric carbon atom and R1 is Η or CH3. 2_ N_oxide as claimed in the scope of claim i, which is substantially free of K[2_(dimethylaminodecyloxyphenyl)ethyl]-cyclohexanol and 1·[2-(dimethyl Amino)_1(4hydroxy-phenyl)ethyl]cyclohexanol, and its 1 〇 tautomers, stereoisomers, salts, hydrates and solvates. 3. If you apply for a patent scope! The oxime-oxides and their tautomers, stereoisomers, hydrates and solvates, wherein R1 is. • N. Oxide as claimed in claim 3, which is substantially free of H2 methylamino) small (4-methoxy-phenyl)ethyl]-cyclohexanol and its 15 5 tautomerism , stereoisomers, salts, hydrates and solvates. N-oxides and their tautomers, stereoisomers, hydrates and solvates of the π patent scope of the invention, wherein Ri is hydrazine. 6 • Ν-oxide as claimed in item 5 of the patent application, which is substantially free of [2-(monomethylamino) small (4-carbyl-phenyl)ethyl]-cyclohexanol and their mutual 〇7 ^isomers, stereoisomers, salts, hydrates, and solvates. 7. The ν_oxide as any of the items in the scope of the patent application, or any of the pharmacologically acceptable salts, hydrates or solvates of 200916092, the quinone% photoactive enantiomer . 5 10 15 8·= The Ν_oxide of item 7 of the patent scope or any of the aforementioned 9 hydrates or solvates which are (8)-enantiomers. An oxide or a pharmacologically acceptable salt, hydrate or solvate of the above item 7, which is the (8)-enantiomer. An N-oxide of item 8 which is substantially free of -methyl-)-1-(4-methoxy.phenyl)ethyl]cyclohexanol and (S)-l-[2 Methylamino) small (4-carbyl-phenylethyl)cyclohexanol and pharmacologically acceptable salts, hydrates and solvates thereof, such as the oxide of the ninth item (iv) of the patent application, which is substantially free (R)-l-[2-(Dimethylamino) small (4-methoxyphenyl)ethyl]-cyclohexanol and (R)-l-[2-methylamino) small (4_ Persyl-phenyl)ethyl}cyclohexanol and pharmacologically acceptable salts, hydrates and solvates thereof. 12. A pharmaceutical agent which comprises a compound ' or a hydrate or solvate thereof according to any one of the claims. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, at least one of the pharmacologically active amounts of at least one of the scope of claims 1-11 A compound, or a hydrate or solvate thereof, as an active ingredient. A combination pharmaceutical preparation comprising (1) a cerium oxide of the formula (1), or a water &amp; or a glutamine compound thereof, and (ii) another therapeutic agent for simultaneous, separate or sequential use For the treatment of depression including major depression, generalized anxiety disorder, obsessive-compulsive disorder and behavioral disorder, social anxiety disorder, panic 200916092, general depression, diabetic neuropathy, migraine and 'hot flash. 15. The combination pharmaceutical preparation according to claim 14, wherein the other therapeutic agent is venlafaxine or 〇-desmethylvenlafaxine. 5. A compound according to any one of claims 1 to 11 for use in the treatment of depression including major depression, generalized anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder , general depression, diabetic neuropathy, migraine and 'hot tide'. A use of a compound according to any one of claims 1 to 11 for the preparation of a pharmaceutical composition for treating depression, generalized anxiety including major depression Symptoms, obsessive-compulsive and behavioral disorders, social anxiety, panic disorder, general camping, diabetic neuropathy, migraine and 'hot tide'. 18. Use of a combination preparation as claimed in claim 15 for the preparation of a pharmaceutical composition for treating depression including depression, generalized anxiety, obsessive-compulsiveness and Behavioral disorders, social anxiety, panic disorder, general camping, diabetic neuropathy, migraine and 'hot tide'. 19. A process for the preparation of a compound according to claim 1, characterized in that the compound of the formula (8) is oxidized with an oxidizing agent to produce a compound of the formula (1) 42 200916092 t 43 200916092 VII. Designation of representative drawings: (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: OH (1) 0