KR20100040881A - N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs - Google Patents

Abstract

The invention concerns venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide as prodrugs of venlafaxine 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 Ris H or CH, 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 venlafaxine.

Description

N-oxides of venlafaxine and O-desmethylvenlafaxine as prodrugs {N-OXIDES OF VENLAFAXINE AND O-DESMETHYLVENLAFAXINE AS PRODRUGS}

Index page

Name of invention 1

Index 1

Technical Field 1

Background technology 2

Specification 3

Definition 6

Example 1 Assay Method 8

Example 2: Synthesis of Specific Compounds 11

Example 3: Pharmacological Method 16

Example 4: Pharmacokinetic and Pharmacological Test Results 18

Example 5: Pharmaceutical Formulations 20

References 23

Claim 24

Summary 28

FIELD OF THE INVENTION The present invention relates to the field of pharmaceuticals and organic chemistry, and as the prodrugs of venlafaxine and its main (active) metabolite O-desmethylvenlafaxine, respectively, venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide, And tautomers, stereoisomers, hydrates and solvates thereof, as well as pharmaceutical compositions containing the compounds, methods for their preparation, and methods for preparing said compositions.

Formula 1

In the above formula (1)

An asterisk (*) denotes an asymmetric carbon atom,

R ¹ is H or CH ₃ .

Venlafaxine is a phenethylamine bicyclic derivative that is chemically independent of tricyclic, tetracyclic or other available antidepressants. Its (-)-enantiomers have been reported to be more potent inhibitors of norepinephrine synaptosome uptake, while their (+)-enantiomers have been reported to be more selective in inhibiting serotonin uptake (Howell, 1994). Venlafaxine is sold as a racemate.

(±) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] -cyclohexanol, venlafaxine

[US Pat. No. 4,761,501; Pento, 1988]

The mechanism of antidepressant action of venlafaxine in humans is considered to be related to its synergism of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. O-desmethylvenlafaxine is the only major active metabolite. Other metabolites are N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine (Klamerus, 1992). O-desmethylvenlafaxine succinate is in the final stage of its development and has recently received an approve from the FDA for the treatment of major depressive disorders. The compound is also under development as a treatment for vasomotor symptoms associated with menopause.

N-oxides have been known since 1894. To date, N-oxides are metabolites of many tertiary amines and in most cases are also well known as intermediates between tertiary amines and N-dealkylated homologs. Most, but not all, tertiary amine drugs give rise to N-oxides. This is the case, for example, in morphine, imipramine, promazine, cinnarizine and nicotine. The extent to which N-oxidation occurs varies from trace to almost quantitative conversion. Some N-oxides were shown to be more potent than their corresponding tertiary amines. The most famous of these is chlordiazepoxide (Librium ^® ), one of the most frequently used drugs in psychiatry and general medicine. In more cases, however, N-oxides are identified with lower potency than their corresponding tertiary amines, and N-oxidation is most commonly considered to be metabolic inactivation. While N-oxides are readily reduced to their corresponding tertiary amines by chemical means, in the human body this varies in degree of occurrence. Some N-oxides undergo almost quantitative reductive conversion to the corresponding tertiary amine, and in other cases the conversion is only present in trace reactions or even completely (Bickel, 1969). Thus, the formation of N-oxides and their corresponding tertiary amines is unpredictable. Generally formed N-oxides may be more active, less active, or even completely inert than their corresponding tertiary amines. N-oxides may or may not be reduced to the corresponding tertiary amine. If they are reduced, the reaction can be only trace or almost quantitative

Since Paracelsus ('Sola dosis facit venerium'), it is generally accepted that the therapeutic effects as well as the toxic effects of drugs are related to their concentration at the relevant target site. Since the latter is generally not easy to obtain, plasma levels are used as an approximation of the relevant drug concentration. Suitable plasma concentration ranges during drug development are defined to provide a lower or lower range for efficacy and an upper range in which side effects are evident. In ideal circumstances, the two concentrations are so far apart that it is easy to administer the drug in a way that is effective but does not cause side effects. In practice, the situation is rarely ideal, and most drugs have side effects. In most cases, the occurrence of side effects may be associated with peak plasma concentrations above the low levels associated with the occurrence of side effects. Venlafaxine produces the highest plasma concentrations causing side effects. Side effects that are most commonly observed with incidence of venlafaxine (> 5% incidence) and that do not show the same rate of occurrence in placebo-treated patients (ie, incidence in venlafaxine are more than twice that of placebo) are associated with persistent hypertension, headache , Weakness, sweating, vomiting, constipation, drowsiness, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or blurred vision, and abnormal ejaculation / orgasm or erectile dysfunction in men. Physicians' Desk Reference, 1999; Sinclair, 1998]. These side effects can significantly limit the dose level, frequency, and duration of drug therapy. Side effects can be attenuated using sustained release formulations (venlafaxine XR), but other compounds can also solve the problem. Therefore, it would be desirable to find a compound having its advantages while avoiding the disadvantages of venlafaxine. Prodrugs have the same pharmacokinetic profile but have a more preferred pharmacokinetic profile.

For oral administration, venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide act as prodrugs, which are rapidly converted to their parent compounds venlafaxine and O-desmethyl-venlafaxine, respectively. The present invention relates to N-oxides of formula 1 and tautomers, stereoisomers, hydrates and solvates thereof.

Formula 1

In the above formula (1)

An asterisk (*) denotes an asymmetric carbon atom,

R ¹ is H or CH ₃ .

The N-oxides of the present invention may be substantially free of venlafaxine and O-desmethylvenlafaxine, and their tautomers, stereoisomers, salts, hydrates and solvates. Venlafaxine N-oxides and O-desmethylvenlafaxine N-oxides can be prepared by oxidizing venlafaxine or O-desmethylvenlafaxine with a suitable oxidizing agent such as m-CPBA. The present invention relates to racemates, mixtures of diastereomers and individual stereoisomers of the N-oxides of the present invention as well as hydrates and solvates thereof.

The invention particularly relates to the N-oxides of formula (1) wherein R ¹ is CH ₃ .

Another preferred embodiment of the invention is an N-oxide of formula 1 wherein R ¹ is H.

Another preferred embodiment is the (S)-and (R) -enantiomers of the N-oxides of formula (1).

Venlafaxine-N-oxide and a composition comprising the same-although side effects-can be effectively treated with venlafaxine: depression, including major depressive disorder, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depression It is useful for treating disorders, diabetic neuropathy, migraine headaches, and vasomotor syndromes associated with menopause, also referred to as 'hot flashes'.

The invention also

Pharmaceutical compositions for treating a disorder or condition treatable by, for example, venlafaxine, comprising an N-oxide of Formula 1 and a pharmaceutically acceptable carrier;

A method of treating a disorder or condition treatable by venlafaxine, comprising administering an N-oxide of Formula 1 to a mammal in need thereof;

A method of treating a disorder or condition treatable by venlafaxine, comprising administering an N-oxide of Formula 1 to a mammal in need thereof;

Pharmaceutical compositions for treating a disorder or condition treatable by venlafaxine, including an N-oxide of Formula 1 and a pharmaceutically acceptable carrier; And

A method of treating a disorder or condition treatable by venlafaxine, comprising administering an N-oxide of Formula 1 to a patient in need thereof.

The invention also provides the use of an N-oxide of formula 1 for the manufacture of a medicament.

The present invention also provides a method of treating a compound of the present invention or a pharmaceutical composition or formulation comprising a compound of the present invention with another therapeutic or therapeutic agent, for example venlafaxine or O-desmethyl-venlafaxine, to treat one or more conditions listed. And concurrently or sequentially, or as a combination therapy. Such other therapeutic agent (s) may be administered before, concurrently with, or after administration of the compound of the invention.

The present invention also provides compounds, pharmaceutical compositions, kits and methods for treating a disorder or condition treatable by venlafaxine, the method comprising administering an N-oxide of Formula 1 to a patient in need of such treatment do.

The present invention also provides methods for preparing the compounds of the present invention and intermediates used in such methods.

Compounds of the present invention contain asymmetric centers. This will produce two optical isomers. All possible optical isomers and diastereomers as pure or partially purified compounds as mixtures belong to the present invention. The present invention includes all such isomeric forms of these compounds. Formula 1 represents a class of compounds without preferred stereochemistry. Independent synthesis of such diastereomers or chromatographic separation thereof can be accomplished as is known in the art by appropriately modifying the methods described herein. Its absolute stereochemistry can, if necessary, be determined by X-ray crystallography of crystalline products or crystalline intermediates induced by reagents containing asymmetric centers of known absolute configuration. The racemic mixture of the compounds can be separated into enantiomers by methods known in the art, for example, the racemic mixture of compounds can be coupled to an enantiomerically pure compound to form a diastereomer mixture and then The individual diastereomers are separated by standard methods such as fractional crystallization or chromatography. The cleavage of the added chiral residues can then convert the diastereomeric derivatives to pure enantiomers. Racemic mixtures of compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents in known arrangements well known in the art.

Some crystalline forms for the compounds may exist as polymorphs and are intended to belong to the invention, for example. In addition, some compounds may form solvates with water (ie, hydrates) or may form solvates with common organic solvents. Such solvates also fall within the scope of the present invention.

Isotopically-labeled N-oxides of formula (1) detectable by PET or SPECT are also within the scope of the present invention. [ ¹³ C]-, [ ¹⁴ C]-, [ ³ H]-, [ ¹⁸ F]-, [ ¹²⁵ I]-or other isotopically enriched atoms suitable for receptor binding or metabolism studies The same applies for N-oxides.

The possibility of discovering that N-oxides of venlafaxine and O-desmethylvenlafaxine are useful as prodrugs of their respective parent compounds has been linked to the clinical benefits of prolonged duration of action and blunted peak plasma concentrations resulting in enhanced side effects profiles. Together offers the possibility of using these compounds as an alternative. Thus, in some embodiments of the present invention, the compounds of the present invention comprise parent compound 1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] -cyclohexanol, venlafaxine or O-desmethylvenlafaxine. It may be provided without substantially containing it. Substantially free means that the compounds of the present invention contain less than about 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1% or less than 0.5% venlafaxine or O-desmethylvenlafaxine as impurities. It means that it does not contain or in the detectable range. Pharmaceutical compositions containing substantially N-oxides of venlafaxine and / or O-desmethylvenlafaxine without substantially containing venlafaxine and / or O-desmethylvenlafaxine are contemplated in accordance with the present invention.

Justice

As used herein, the term “venlafaxine” means a racemic compound (R, S) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol.

Any compound that is metabolized in vivo to provide a bioactive agent (ie, a compound of Formula 1) is a prodrug within the scope and scope of the application. Prodrugs are therapeutic agents that are originally inert but are modified with one or more active metabolites. Thus, in the methods of treatment of the present invention, the term “administration” will include treating the various disorders described with a specifically described compound or a compound that is not specifically described but converted to a specific compound in vivo after administration to a patient. Prodrugs are bioreversible derivatives of drug molecules used to overcome some obstacles to the use of parent drug molecules. These disorders include, but are not limited to, solubility, permeability, stability, systemic metabolism, and subject limitations. Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; Jarvinen, 2005]. Prodrugs, ie compounds that are administered to humans by any known route and metabolized to compounds of Formula 1, are within the invention. In particular it relates to a hydroxy group which can be reacted with an organic acid to give a compound of formula 1, wherein an additional group which is easily removed after administration, including but not limited to amidine, enamine, Mannich Bases, hydroxyl-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enamiminones are present.

The term "polymorphism" is defined as the ability of a compound to exist in one or more crystalline forms called so-called polymorphs. Polymorphism is a frequent phenomenon. Polymorphism is affected by several crystallization conditions, such as temperature, supersaturation level, presence of impurities, polarity of solvent or cooling rate. Polymorphism can be characterized by several methods, for example, solid state NMR, solubility test, DSC or melting point measurement, IR or Raman spectroscopy.

To provide a more concise description, some quantitative expressions provided herein do not involve the term "about." All terms described herein, whether or not the term "about" is explicitly used, mean substantially the values provided, and also include approximations due to experimental and / or measurement conditions for such provided values and refer to general techniques in the art. It means an approximation to these provided values which are reasonably inferred on the basis. Throughout the description and claims of this specification, the word "comprises" and variations thereof, such as "comprises" and "comprising", are not intended to exclude other additives, components, integers, or steps. As used herein, the term "composition" includes any product resulting from combining certain components in a specific amount, directly or indirectly, as well as products comprising certain components in a predetermined amount or proportion. In the context of pharmaceutical compositions, the term refers to the combination of two or more components, the combination of two or more components, the dissociation of one or more components, or one or more components, as well as any carrier comprising one or more active ingredients, and any carrier comprising inactive components. It includes any product that causes a reaction or interaction of other types of components. In general, pharmaceutical compositions are prepared by associating the active ingredient with a single, intimate liquid carrier or finely divided solid carrier, or both, and if necessary, shaping the product into the desired formulation. The pharmaceutical composition comprises sufficient activity of the desired compound to produce the desired effect on the progress or condition of the disease. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

In the context of the present specification, the term “combination formulation” refers to typical combinations, such as tablets or injection emulsions, as well as instructions for use, which refer to N-oxides of Formula 1 and other agents that are physically formulated in one formulation. Two 'part kits' comprising the N-oxide and venlafaxine of Formula 1 or another medicament, in separate dosage forms, optionally together with additional means for facilitating the administration of the constituent compounds, for example, a label or a picture. Contains different. In typical combinations, by definition pharmacotherapy exists simultaneously. The contents of the 'part kit' can be administered simultaneously or at different time intervals. Simultaneous or sequential treatment will depend on the nature of the disease, its stage, and the individual patient, as well as the characteristics such as the onset and duration of the specific action of the other agents used, plasma levels, clearance and the like.

"Pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and should not be harmful to its recipient.

Dose: The recommended therapeutic dose is the same as venlafaxine: 75 mg / day, administered in two or three separate doses, and taken with food. Pharmacokinetics, pharmacodynamics and other considerations can substantially alter the administered dose to higher or lower values. The dose of compound to be administered will depend on the relevant indication, the age, weight and sex of the patient, and can be determined by the physician. The dose will preferably range from 0.01 mg / kg to 10 mg / kg. Typical daily doses of active ingredients will vary widely and will depend on various factors, such as the relevant instructions, route of administration, age, weight and sex of the patient, as determined by the physician. Generally, oral and parenteral dosages will range from 0.1 to 1,000 mg / day of total active ingredient.

As used herein, the term “therapeutically effective amount” means an amount of therapeutic agent that treats or prevents a condition treatable by administering a composition of the present invention. Such amount is an amount sufficient to produce a detectable therapeutic, prophylactic or palliative response in the tissue system, animal or human. The effect may include, for example, treating or preventing the conditions listed herein. The exact effective amount for a subject depends on the subject's size and health, the nature and extent of the condition being treated, the recommendations of the treating physician (researcher, veterinarian, medical doctor, or other clinician) and the combination of therapeutic or therapeutic agents selected for administration. Will be influenced. Therefore, it is not useful to limit the exact effective amount in advance.

As used herein, the term “treatment” means any treatment of a mammal, preferably a human condition or disease, and (1) a disease or condition that can occur in a subject that is susceptible to disease but has not yet been diagnosed with the disease. Prophylaxis, (2) inhibition of the disease or condition, i.e. stopping its development, (3) alleviation of the disease or condition, i.e. inducing regression of the condition or (4) discontinuation of symptoms of the disease. As used herein, the term “medical therapy” is intended to include prophylactic, diagnostic and therapeutic plans performed on humans or other mammals in vivo or ex vivo. As used herein, the term “subject” means an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment.

Example 1 Assay Method

Nuclear magnetic resonance spectra ( ¹ H NMR and ¹³ C NMR, APT) were measured at 300 K using Bruker DRX 600 ( ¹ H: 600 MHz, ¹³ C: 150 MHz) in the indicated solvents unless otherwise indicated It was. Spectra were measured in deuterated DMSO purchased from Cambridge Isotope Laboratories Ltd. Chemical shifts (δ) are given in ppm low fields from tetramethylsilane ( ¹ H). Coupling constant J is given in Hz. The peak shape in the NMR spectrum is symbol 'q' (quadruid), 'dq' (duplex quadruple), T (triple triplet), 'dt' (duplex triplet), 'd' (duplex), 'dd' (Double duplex), 's' (single line), 'bs' (wide single line), and 'm' (multiple line). NH and OH signals were identified after mixing the sample by dropwise addition of D ₂ O.

Melting points were recorded with a Buchi B-545 melting point apparatus.

Flash chromatography means purification using the indicated eluent and silica gel (Acros: 0.030 to 0.075 mm or Merck silica gel 60: 0.040 to 0.063 mm).

The reaction was monitored using thin layer chromatography (TLC) on a silica coated plastic sheet (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualized by UV light (254 nm) or I ₂ .

Liquid chromatography-mass spectrometry (LC-MS) was performed using a system consisting of two Perkin Elmer series 200 micro pumps. The pumps were connected to each other with a 50 μl tee mixer connected to a Gilson 215 auto sampler. Here's how:

The auto sampler has a 2 μl injection loop. The auto sampler is connected to a Waters Atlantis C18 30 * 4.6 mm column of 3 μm particles. The column is heat controlled to 40 ° C. in a Perkin Elmer Series 200 column oven. The column is connected to a Perkin Elmer Series 200 UV with 2.7 μl flowcell. The wavelength is set to 254 nm. The UV meter is connected to the Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: scan range: 150-900 amu; Polarity: positive; Scanning method: profile; Resolution Q1: UNIT; Step size: 0.10 amu; Time per injection: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10. Connect the light scattering detector to the Cyx API 150. The light scattering detector is Sedere Sedex 55 operating at 50 ° C. and 3 bar N ₂ . The complete system is controlled by a G3 PowerMac.

Venlafaxine and its N-oxides were analyzed in mouse plasma and brain samples using HPLC with general bioanalytical methods including protein precipitation and MS / MS detection.

Protein in 100 μL plasma was precipitated with acetonitrile and 5 μL sample of the resulting solution was analyzed. Complete brains were homogenized, centrifuged and 10 μl of supernatant samples analyzed.

Liquid Chromatography-Tandem mass spectrometry (LC-MS / MS) was performed using a Cyx API4000 LC-MS / MS. Samples were quantified using extracted calibration samples that were treated identically to study samples ranging from 1 to 5000 ng / ml and 5.0 to 5000 ng / brain for plasma and brain samples, respectively. Compound peak areas were used for quantification. The calibration curve is model y = A + Bx + Cx ² , where y is the peak area of the analyte, x is the normal calibration level of ng / ml (plasma) or ng / g (brain), A is the segment, B Is the slope, and C is the plot of curvature). 1 / x ² weight was used. LC-MS / MS system performance was monitored using reference solutions injected at standard intervals. The method has not been validated in detail and therefore the reported concentrations are good estimates. Minimum limit of quantification (LLOQ) was assessed at 1.00 ng / ml and 5.00 ng / brain for plasma and brain samples, respectively. Values below the LLOQ were given as best estimates. Reverse phase HPLC was performed at 45 ° C. with a flow rate of 1.00 mL / min using a gradient elution with a Hypersil BDS C18 100 × 4.6 mm 3 μm analytical column.

Detection on MS / MS was performed using positive MRM ionization. The ions measured are as follows:

Venlafaxine Venlafaxine-N-oxide

Q1 278.3 294.5

Q3 121.1 121.1

Example 2: Synthesis of Specific Compounds

(R, S) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] -cyclohexanol (venlafaxine) and (R, S) -1- [2- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] -cyclohexanol (O-desmethylvenlafaxine) was synthesized as described in EP 1 721 889. Alternatives to the latter are provided below.

(R, S) -1- [2-Oxido- (dimethylamino) -1- (4-methoxyphenyl) ethyl] -cyclohexanol (venlafaxine N-oxide):

Venlafaxine (0.28 g, 1.02 mmol) was dissolved in 20 mL of DCM and cooled to -10 ° C. Meta-chloroperbenzoic acid (m-CPBA, 0.8 g, 2.02 mmol) was added to the reaction mixture, and the solution was stirred at −10 ° C. for 30 minutes. Solid K ₂ CO ₃ (2 g) was added and the resulting mixture was stirred at 0 ° C. for an additional 30 minutes. The reaction mixture was filtered (glass funnel) and the precipitate was carefully washed with DCM. The resulting solution was concentrated and purified by flash chromatography (SiO ₂ , DCM / MeOH (after 95/5, 9/1)) to give the title compound as a solid (0.22 g, 74%). mp 145 ° C. LCMS; R _t : 1.12 min, ([M + H] ⁺ = 294).

(R, S) -1- [2-Oxido- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] -cyclohexanol (O-desmethylvenlafaxine N-oxide) may be prepared in the same manner. Can be.

(S)-and (R) -enantiomers of venlafaxine, their respective N-oxides and O-desmethyl homologues were synthesized as shown in the scheme below.

(R, S) -1- (2- (dimethylamino) -1- (4-methoxyphenyl) ethyl) cyclohexanol (venlafaxine, 10):

Cyclohexanol (33 g, 0.13 mol) was dissolved in formic acid (99%, 54 mL, 1.43 mol) to which formaldehyde (37%, 41 mL, 1.48 mol) was added and water (330 mL). The mixture was refluxed for 2 hours. The reaction mixture was concentrated to 150 mL (pH-1.0), water (100 mL) was added, and the mixture was extracted with ethyl acetate (4 x 100 mL). The aqueous layer was cooled in an ice bath and the pH was basified to ˜10 by addition of 50% NaOH. The mixture was extracted with ethyl acetate (3 x 100 mL), dried over Na ₂ S0 ₄ and concentrated. Yield: The material (23.8 g, main compound 11) was suspended in diethyl ether (500 mL) and treated with lithium aluminum hydride (3.8 g, 0.1 mol). The suspension was stirred for 18 hours at room temperature. 5N KOH (16 mL) was added carefully and the mixture was stirred for 15 minutes. The solid was removed by filtration over celite and washed (diethyl ether, 300 mL). The filtrate was dried (sodium sulfate) and concentrated. Yield: 21.4 g (60%) of compound 10 as a white solid.

R-venlafaxine (compound 2 in the above scheme):

(R, S) -venlafaxine (23.4 g, 84 mmol) was dissolved in ethyl acetate (160 mL). To the solution was added a solution of D-ditoluyl-tartaric acid (18.7 g, 48 mmol) in ethyl acetate (130 mL). Within 10 minutes salt began to precipitate. The mixture was stirred at rt for 4 h. The precipitate was collected by filtration with a glass filter and washed with ethyl acetate (2 x 100 mL). White crystalline solid. The solid was recrystallized from ethyl acetate: methanol (6: 1, 100 mL). The solid was collected on a glass filter. Yield 14.0 g. The material was treated with 2N NaOH (cold, 180 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with 2N NaOH (cold, 75 mL) followed by water until the wash was neutral (pH 7). The organic phase was dried (sodium sulfate) and concentrated. Yield: 8.1 gmp of R- venlafaxine (2) as a white crystalline solid: 106 ° C-109.5 ° C. [a] _D ²³ = -8.0 (c = 1.5, MeOH). Chiral HPLC: 99% ee ¹ H-NMR (CDCl ₃ ): see above.

S-venlafaxine (1)

The mother liquor of the lysate (see above) was removed by washing with 1N NaOH (4 × 100 mL), water (3 × 200 mL) and brine (100 mL). The organic phase was dried (sodium sulfate) and concentrated. The oil solidified quickly. The material was redissolved in ethyl acetate (75 mL). A solution of L-ditoluyl tartaric acid (11.3 g, 29 mmol) in ethyl acetate (75 mL) was added. Precipitation began within 5 minutes. Ethyl acetate (50 mL) was added and the mixture was stirred at rt for 72 h. The solid was collected on a glass filter. Yield: 14.2 g. The material was treated with 2N NaOH (cold, 180 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with 2N NaOH (cold, 75 mL) followed by water until the wash was neutral (pH 7). The organic phase was dried (sodium sulfate) and concentrated. Yield: S-venlafaxine (1) 6.7 gmp 104.5 ° C.-106 ° C. as white crystalline solid. [a] _D ²³ = +13.9 (c = 1.6, MeOH). Chiral HPLC: 98% ee ¹ H-NMR (CDCl ₃ ): see above.

S-venlafaxine N-oxide (3)

Crude material (2.2 g, 7.5 mmol) was obtained by FAI (106796) according to the method described in 4. Pure compound (3) was obtained by column chromatography (gradient dichloromethane: methanol, 9: 1-> dichloromethane: ammonia in 3.5M methanol, 9: 1). Yield: 1.70 g (5.8 mmol, 78%) of compound (3) as a pale yellow solid.

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 -10 ° C. m-CPBA (fresh, 2.9 g, 7.3 mmol) was added. The suspension was stirred for 30 min at -10 ° C. TLC confirmation indicated complete conversion. K ₂ CO ₃ (5.0 g, 36 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. Dichloromethane (50 mL) was added and the suspension was filtered. The filtrate was dried and concentrated. Crude product was purified as above. Yield: 0.9 g (3.0 mmol, 90%) as a white solid. [α] _D ²³ : not measured. ¹ H-NMR (300 MHz, CDCl ₃ ): see above.

O-desmethyl-S-venlafaxine (5):

A solution of diphenylphosphine (18 mL, 0.1 mol) in anhydrous tetrahydrofuran (120 mL) was cooled to -10 ° C under N ₂ . n-BuLi (2.5 M in hexane, 50 mL) and additional tetrahydrofuran (40 mL) were added. The mixture was stirred for 30 min at -10 ° C, then the temperature was increased to 0 ° C. At this temperature, a solution of S-venlafaxine (1, 6.2 g, 23 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred for 2 hours, at which time the temperature was allowed to warm to room temperature and subsequently to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into 2N HCl (cold, 300 mL) and stirred for 10 minutes. The aqueous phase was washed (ethyl acetate, 3 × 300 mL), then neutralized by slow addition of NaHCO ₃ (s) (pH 7) and extracted (ethyl acetate, 6 × 300 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was suspended in ethyl acetate (100 mL) and stirred for 30 minutes. The solid was collected on a glass filter and washed with ethyl acetate until a small amount of diphenylphosphine was no longer detected. White solid. Yield: 4.6 g (17.5 mmol, 76%).

O-desmethyl-R-venlafaxine (6):

As above, starting from R-venlafaxine (5.0 g, 18 mmol), diphenylphosphine (14 mL) and n-BuLi (2.5 M, 41 mL) in hexanes were used. Yield: 3.8 g (14.5 mmol, 80%). mp 235.5 ° C.-237.1 ° C. [a] _D ²³ = -21.3 (c = 0.9, MeOH). ¹ H-NMR (300 MHz, DMSO-d ⁶ ): see above.

O-desmethyl-S-venlafaxine N-oxide (7):

O-desmethyl-S-venlafaxine (5, 1.5 g, 5.7 mmol) was suspended in dichloromethane (100 mL). The suspension was cooled to -10 ° C. m-CPBA (4.8 g, 12 mmol) was added. The suspension was stirred at -10 ° C for 60 minutes. TLC confirmation indicated complete conversion. K ₂ CO ₃ (7.5 g, 54 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. Dichloromethane (100 mL) was added and the suspension was filtered. The residue was stirred in methanol (300 mL) and filtered again. The combined filtrates were concentrated in vacuo (yield 7.1 g). The material was purified by column chromatography: Crude product was dissolved in methanol (20 mL), placed in a column (silica in dichloromethane), eluted with dichloromethane (200 mL) and subsequently eluted with dichloromethane: 7M NH _{3 in} methanol, 9: 1. Yield: 1.15 g (4.1 mmol, 72%) of compound (7) as a pale yellow solid.

O-desmethyl-R-venlafaxine N-oxide (8):

As above, starting from O-desmethyl-R-venlafaxine (6, 1.5 g, 5.7 mmol). Yield: 1.20 g (4.3 mmol, 75%) as a pale yellow solid. [a] _D ²³ = +16.3 (c = 0.8, MeOH). ¹ H-NMR (300 MHz, DMSO-d ₆ ): see above.

Example 3: Pharmacological Method

Neurotransmission using CEW (128, rue Danton, 92500 Rueil-Malmaison, France) or Solvay Pharmaceuticals BV; CJ van Houtenlaan 36, 1381 CP Weesp, The Netherlands In vitro affinity for the material resorption site was obtained. Affinity to serotonin (Tatsumi, 1999), norepinephrine (Pacholczyk, 1991) and dopamine reuptake sites (Pristupa, 1994) was measured.

In Vitro Inhibition of [ ³ H] -Serotonin Resorption: Male rats (Wistar Hsd / Cpb: WU; 175-200 g) were choked, cerebral hemispheres quickly removed, and P2-synaptosome fractions were prepared. Synaptosomes were preincubated in medium containing MAO inhibitor pargiline (7 μm) at 37 ° C. for 15 minutes in the absence or presence of test compounds. Subsequently the synaptosomes were exposed to [ ³ H] -serotonin (0.2 mM final concentration) for 10 minutes. [ ³ H] -Serotonin uptake was stopped by filtration by harvesters and unintroduced radioactivity was removed by extensive washing. The filter plate containing synaptosomes was dehydrated and the amount of [ ³ H] -serotonin present was measured with a Betaplate liquid scintillation counter. The inhibitory effect on the uptake of [ ³ H] -serotonin was expressed as a negative login plC ₅₀ value at a concentration at which half maximal inhibition of radiolabeled neurotransmitter uptake was achieved. The plC ₅₀ values provided are the mean values of 2 to 9 experiments performed in duplicate. Test compounds dissolved at 10 ⁻² M in DMSO were diluted to a test concentration of 10 ⁻⁸ to 10 ⁻⁵ M in Krebs Ringer buffer. Further experimental descriptions are as described (Coyle, 1969).

In Vitro Inhibition of [ ³ H] -norepinephrine reuptake: Male rats (Wistar Hsd / Cpb: WU; 175-200 g) were choked, the hypothalamus rapidly removed, and a coarse synaptosome fraction was prepared. Synaptosomes were preincubated in medium containing MAO inhibitor pargiline (7 μm) at 37 ° C. for 10 minutes in the absence or presence of test compounds. Subsequently, the synaptosomes were exposed to [ ³ H] -norepinephrine (0.4 mM final concentration) for 15 minutes. [ ³ H] -norepinephrine uptake was stopped by filtration by harvesters and the unintroduced radioactivity was removed by extensive washing procedures. The filter plate containing synaptosomes was dehydrated and the amount of [ ³ H] -norepinephrine present was measured with a betaplate liquid scintillation counter. The inhibitory effect on the uptake of [ ³ H] -norepinephrine was expressed as a negative login plC ₅₀ value at the concentration at which half maximal inhibition of radiolabeled neurotransmitter uptake was achieved. The plC ₅₀ values provided are the mean values of 2 to 9 experiments performed in duplicate. Test compounds dissolved at 10 ⁻² M in DMSO were diluted to a test concentration of 10 ⁻⁸ to 10 ⁻⁵ M in Krebs Ringer buffer. Further experimental descriptions are as described (Coyle, 1969).

In Vitro Inhibition of [ ³ H] -Dopamine Resorption: Chop of rats (Wistar Hsd / Cpb: WU; 175-200 g), rapid elimination of striatum, coarse synaptosome fraction (P2) by homogenization and centrifugation ). Synaptosomes were precultured in medium containing the monoamine oxidase inhibitor pargiline (7 × 10 ⁻⁶ M) at 37 ° C. for 15 minutes in the absence or presence of test compounds (Coyle, 1969). Subsequently, [ ³ H] -dopamine (2 × 10 ⁻⁷ M final concentration) was added and incubation continued for 10 minutes. [ ³ H] -dopamine uptake was stopped by filtration and the synaptosomes were washed four times with phosphate buffered saline. The amount of [ ³ H] -dopamine in the synaptosomes was measured with a betaplate liquid scintillation counter. Compounds were tested at concentrations ranging from 10 ⁻⁹ to 10 ⁻⁵ M. The inhibitory effect on the uptake of [ ³ H] -dopamine was expressed using a plC ₅₀ value (negative log of the concentration at which the drug causes 50% inhibition of absorption). Inhibition of DA uptake was performed in duplicate.

Human Colon Model TIM2 (TNO Intestinal Model 2) is a dynamic model for the human colon that simulates in vivo conditions. This is an artificial digestive system proven by many studies (Minekus, 1999).

Venlafaxine-N-oxide is a prodrug of the parent compound. These are venlafaxine-despite their side effects-which are useful in treating diseases that can be treated effectively: depression including major depressive disorders, general anxiety disorders, obsessive-compulsive disorders, social anxiety disorders, panic disorders, general depressive disorders, diabetic neuropathy , Migraine, and vasomotor syndrome associated with menopause, also called 'hot flash'.

Example 4: Pharmacokinetic and Pharmacological Test Results

Venlafaxine and its N-oxide formulated in 40% HPβCD or 1% methylcellulose, respectively (intravenously (iv) or oral (po)) are administered to male NMRI mice (3 animals in time point) , Their plasma and brain were analyzed for both compounds by LC-MS (see method above). Data were averaged (n = 3) and collected in Table 1.

TABLE 1

In mice, venlafaxine was metabolized to its N-oxide in a minimal amount: its concentration in plasma never exceeds 1 to 2% of the concentration of the parent compound and only traces can be found in the brain. When venlafaxine-N-oxide itself was administered, it was reduced to the parent compound. About 1 hour after intravenous administration of venlafaxine-N-oxide, venlafaxine concentrations in plasma and brain exceed that of N-oxide. The effect is more pronounced after oral administration: venlafaxine concentrations in both plasma and brain increase to a factor of 10 to 100 higher than that of N-oxide.

Venlafaxine-N-oxide (1 mg) suspended in 1% methylcellulose was inserted into the lumen (120 mL) of the TIM2 model (see above, Minekus, 1999). Samples and dialysate from the lumen (the latter is a model for the intestinal vascular phase) were taken at various time intervals and analyzed for venlafaxine-N-oxide and venlafaxine:

TABLE 2

From this result, it was reduced almost quantitatively within 2 hours after venlafaxine N-oxide administration. Because many studies demonstrate TIM2 as a high predictive value in vitro model for gastrointestinal conditions in living humans, it is predicted that in humans, after oral administration, venlafaxine N-oxide will be reduced to venlafaxine, which is the prodrug.

[Table 3]

For intravenous administration, the C _max value was extrapolated to T ₀ (0 hours).

The data provided above demonstrated that the clearance, distribution volume and bioavailability of venlafaxine is twice as high as that of its pyridine N-oxide. Clearly, both compounds have different pharmacokinetic properties. As is also evident from the data listed in Table 1, venlafaxine-N-oxide hardly penetrates the brain: therefore the brain / plasma ratio is dramatically different.

The in vitro pharmacological data listed in the table clearly shows that venlafaxine is the most potent as an inhibitor of serotonin reuptake. Its (R)-and (S) -enantiomers showed only slight differences. The major metabolite, O-desmethylvenlafaxine, was found to be comparable to venlafaxine as both racemate and its individual enantiomeric form. It has been found that the N-oxides of venlafaxine and O-desmethyl-venlafaxine as individual (R)-or (S) -enantiomers, as well as racemates, are virtually lacking in activity.

Example 5: Pharmaceutical Formulations

For clinical use, the N-oxides of Formula 1 are formulated into pharmaceutical compositions, which are an important and novel aspect of the present invention because they contain compounds, more particularly certain compounds described herein. Types of pharmaceutical compositions that can be used include tablets, chewable tablets, capsules (including microcapsules), solvents, parenteral solutions, ointments (creams and gels), suppositories, suspensions and other types described herein It will be apparent to those skilled in the art from the specification and general knowledge in the art. For example, the active ingredient may also be in the form of inclusion complexes in cyclodextrins, ethers thereof or esters thereof. The composition is used for administration by oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, oral, rectal, parenteral or other modes of administration. Pharmaceutical formulations contain one or more N-oxides of Formula 1 as a mixture with one or more pharmaceutically acceptable adjuvants, diluents and / or carriers. The total amount of active ingredient suitably ranges from about 0.1 to about 95% (w / w), suitably from 0.5 to 50% (w / w), preferably from 1 to 25% (w / w) of the formulation. In some embodiments, the amount of active ingredient is greater than about 95% (w / w) or less than about 0.1% (w / w).

Compounds of the present invention may be used as auxiliary ingredients such as liquid or solid, powdered ingredients such as pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavors, colorants and / or buffer components. It can be made into a form suitable for administration in a conventional process using. Frequently used auxiliary ingredients include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugar or sugar alcohols, talc, milk protein, gelatin, starch, amylopectin, cellulose and derivatives thereof, animal and vegetable oils, for example For example, fish liver oil, sunflower oil, peanut oil, sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol, as well as disintegrants and lubricants such as magnesium stearate Latex, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets are made using the following ingredients:

Ingredient amount (mg / tablet)

Venlafaxine N-oxide 10

Cellulose, Microcrystalline 200

Silicon Dioxide, Fumed 10

Stearic acid                       10

Total 230

The ingredients are mixed and compressed to form tablets, each weighing 230 mg.

The active ingredient may be premixed separately with other inactive ingredients prior to mixing to form the formulation. The active ingredients may also be mixed with each other before mixing with the inactive ingredients to form the formulation.

Soft gelatin capsules can be made into capsules containing mixtures of the active ingredients of the invention, vegetable oils, fats or other vehicles suitable for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules may also contain the active ingredient in combination with solid powder ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may comprise (i) suppository forms containing the active ingredient mixed with triglyceride bases; (ii) a gelatin rectal capsule form containing the active ingredient in a mixture with a vegetable oil, paraffin oil or other vehicle suitable for a gelatin rectal capsule; (iii) ready-made micro enema, or (iv) anhydrous micro enema, which is reconstituted in a suitable solvent immediately prior to administration.

Liquid preparations include syrups, elixirs, concentrated dropping agents or suspensions, for example solutions containing the active ingredient and, for example, sugars or sugar alcohols, and mixtures of ethanol, water, glycerol, propylene glycol and polyethylene glycol Or in suspension form. If desired, such liquid preparations may contain colorants, flavors, preservatives, saccharin and carboxymethyl cellulose or other thickeners. Liquid formulations may also be prepared in anhydrous powder form which is reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as formulation solutions of the present invention in pharmaceutically acceptable solvents. These solutions may also contain stabilizing, preserving and / or buffering components. Solutions for parenteral administration can also be prepared as anhydrous powders which are reconstituted with a suitable solvent before use.

Also provided is a 'part kit' comprising a formulation and one or more containers filled with one or more components of the pharmaceutical composition of the invention for use in medical treatment according to the invention. Such container (s) regulate the manufacture, use, or sale of pharmaceutical products, reflecting various written materials, such as instructions for use, or approval by the agency of manufacture, use, or sale for human or veterinary administration. May be associated with a form of notification prescribed by a government agency. Drugs for the treatment of depression, including major depressive disorders, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depressive disorder, diabetic neuropathy, migraine, and menopausal syndrome associated with menopause, also referred to as 'hot flash' Use of the formulations of the invention in the preparation of a therapeutically effective amount of at least one N-oxide of Formula 1, including depression, general anxiety disorders, obsessive-compulsive disorders, social anxiety disorders, panic disorders, general depressive disorders, including major depressive disorders And diabetic neuropathy, migraine, and post-administration to a patient suffering from vasomotor syndrome associated with menopause, also referred to as 'hot flash', in the case of prodrugs.

Without limitation in the manner of the examples, several pharmaceutical compositions are provided comprising the preferred active compounds for systemic use or topical application. Other compounds of the present invention or combinations thereof may be used in place of (or in addition to) the compounds. The concentration of the active ingredient can vary over the wide range discussed herein. The amount and type of ingredients that can be included is well known in the art.

References

In order to expand the usefulness of the following references to those skilled in the art or to more fully explain the present invention, they are incorporated herein by reference. These or any other documents or citations described herein, or citations to any references, are not accepted as prior art documents or citations.

Claims (19)

N-oxides of formula 1 and their tautomers, stereoisomers, hydrates and solvates thereof.
Formula 1

In Formula 1 above,
An asterisk (*) denotes an asymmetric carbon atom,
R ¹ is H or CH ₃ . The compound of claim 1, wherein 1- [2- (dimethylamino) -1- (4-methoxy-phenyl) ethyl] -cyclohexanol and 1- [2- (dimethylamino) -1- (4-hydroxy N-oxide and its tautomers, stereoisomers, salts, hydrates and solvates substantially free of -phenyl) ethyl] -cyclohexanol. The N-oxide and its tautomer, stereoisomer, hydrate and solvate of claim 1, wherein R ¹ is CH ₃ . The N-oxide and its tautomeric, stereoisomer thereof according to claim 3, which is substantially free of 1- [2- (dimethylamino) -1- (4-methoxy-phenyl) ethyl] -cyclohexanol , Salts, hydrates and solvates. The N-oxide and its tautomers, stereoisomers, hydrates and solvates according to claim 1, wherein R ¹ is H. The N-oxide and its tautomeric, stereoisomer thereof according to claim 5, which is substantially free of 1- [2- (dimethylamino) -1- (4-hydroxy-phenyl) ethyl] -cyclohexanol , Salts, hydrates and solvates. The N-oxide or pharmacologically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 6, wherein the compound is an optically active enantiomer. The N-oxide or pharmacologically acceptable salt, hydrate or solvate thereof according to claim 7, which is (R) -enantiomer. The N-oxide or pharmacologically acceptable salt, hydrate or solvate thereof according to claim 7, which is (S) -enantiomer. The compound of claim 8, wherein (S) -1- [2- (dimethylamino) -1- (4-methoxy-phenyl) ethyl] -cyclohexanol and (S) -1- [2- (dimethylamino) N-oxides or pharmacologically acceptable salts, hydrates and solvates thereof, substantially free of -1- (4-hydroxy-phenyl) -ethyl] -cyclohexanol. A compound according to claim 9, wherein (R) -1- [2- (dimethylamino) -1- (4-methoxy-phenyl) ethyl] -cyclohexanol and (R) -1- [2- (dimethylamino) N-oxide or a pharmacologically acceptable salt, hydrate and solvate thereof, substantially free of -1- (4-hydroxy-phenyl) -ethyl] -cyclo hexanol. 12. A pharmaceutical comprising a compound according to any one of claims 1 to 11 or a hydrate or solvate thereof. In addition to the pharmaceutically acceptable carrier and / or one or more pharmaceutically acceptable auxiliary ingredients, the active ingredient comprises an pharmacologically active amount of at least one compound of any one of claims 1 to 11 or a hydrate or solvate thereof. Pharmaceutical composition. For use simultaneously, separately or sequentially in the treatment of depression, including major depressive disorders, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depressive disorder, diabetic neuropathy, migraine and 'hot flash' A pharmaceutical combination formulation comprising N-oxide of Formula 1, or a hydrate or solvate thereof (i) and another therapeutic agent (ii). The pharmaceutical combination formulation according to claim 14, wherein the other therapeutic agent is venlafaxine or O-demethylvenlafaxine. The treatment of depression, including general depressive disorder, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depressive disorder, diabetic neuropathy, migraine and 'hot flash' The compound claimed in any one of the claims. For the manufacture of pharmaceutical compositions for treating depression, including general depressive disorder, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depressive disorder, diabetic neuropathy, migraine and 'hot flash' Use of a compound as claimed in claim 1. The method of claim 15, wherein the pharmaceutical composition for the treatment of depression, including general depressive disorder, general anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, general depressive disorder, diabetic neuropathy, migraine and 'hot flash' For the use of a combination formulation. A process for preparing a compound as claimed in claim 1, characterized in that the compound of formula a is oxidized with an oxidizing agent to give the compound of formula 1.