WO2009000797A1 - N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs - Google Patents
N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs Download PDFInfo
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- WO2009000797A1 WO2009000797A1 PCT/EP2008/057939 EP2008057939W WO2009000797A1 WO 2009000797 A1 WO2009000797 A1 WO 2009000797A1 EP 2008057939 W EP2008057939 W EP 2008057939W WO 2009000797 A1 WO2009000797 A1 WO 2009000797A1
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- oxide
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- venlafaxine
- solvates
- hydrates
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- PNVNVHUZROJLTJ-MRXNPFEDSA-N CN(C)C[C@@H](C1(CCCCC1)O)c(cc1)ccc1OC Chemical compound CN(C)C[C@@H](C1(CCCCC1)O)c(cc1)ccc1OC PNVNVHUZROJLTJ-MRXNPFEDSA-N 0.000 description 2
- PNVNVHUZROJLTJ-INIZCTEOSA-N CN(C)C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC Chemical compound CN(C)C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC PNVNVHUZROJLTJ-INIZCTEOSA-N 0.000 description 2
- CSDSVBNRENNXMJ-MRXNPFEDSA-N C[N](C)(C[C@@H](C1(CCCCC1)O)c(cc1)ccc1OC)[O-] Chemical compound C[N](C)(C[C@@H](C1(CCCCC1)O)c(cc1)ccc1OC)[O-] CSDSVBNRENNXMJ-MRXNPFEDSA-N 0.000 description 2
- SRNWVXSHSZVCKN-INIZCTEOSA-N C[N](C)(C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC)O Chemical compound C[N](C)(C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC)O SRNWVXSHSZVCKN-INIZCTEOSA-N 0.000 description 1
- CSDSVBNRENNXMJ-INIZCTEOSA-N C[N](C)(C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC)[O-] Chemical compound C[N](C)(C[C@H](C1(CCCCC1)O)c(cc1)ccc1OC)[O-] CSDSVBNRENNXMJ-INIZCTEOSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- Example 4 Pharmacokinetic and pharmacological test results 18
- Example 5 Pharmaceutical preparations 20
- This invention relates to the fields of pharmaceutical and organic chemistry, and provides venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide, having formula (1 ):
- Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents. It has been reported that its (-)-enantiomer is a more potent inhibitor of norepinephrine synaptosomal uptake while its (+)-enantiomer is more selective in inhibiting serotonin uptake (Howell, 1994). Venlafaxine is marketed as racemate. i
- venlafaxine and its major metabolite 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 a late stage of its development, and recently received an approvable letter from the FDA for the treatment of Major Depressive Disorder. The compound is also in development as treatment of vasomotor symptoms associated with menopause.
- N-oxides are known since 1894. By now it is very well known that N-oxides are metabolites of many tertiary amines, and in most cases are also intermediates between tertiary amines and their N-dealkylated analogs. Most, but not all, tertiary amine drugs give rise to N-oxides. This is for instance the case with morphine, imipramine, promazine, cinnarizine and nicotine. How much N-oxidation takes place varies from trace amounts to a nearly quantitative conversion. Some N-oxides were shown to be more potent than their corresponding tertiary amines.
- N-oxides were found to be less potent than their corresponding tertiary amines, and N-oxidation is most commonly regarded to be metabolic deactivation. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines and in other cases the conversion is a mere trace reaction or even completely absent (Bickel, 1969).
- N-oxides and their corresponding tertiary amines are unpredictable. Once formed, N-oxides may be more active than their corresponding tertiary amines, less active or even completely inactive. N-oxides may be reduced to the corresponding tertiary amines or not. When they are, the reaction may be a mere trace or nearly quantitative.
- Venlafaxine produces peak plasma concentrations resulting in side effects.
- adverse events associated with the use of venlafaxine include sustained hypertension, headache, asthenia, sweating, nausea, constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or blurry vision, and abnormal ejaculation/orgasm or impotence in males (Physicians' Desk Reference, 1999; Sinclair, 1998). These adverse effects can significantly limit the dose level, frequency, and duration of drug therapy.
- Adverse events can be attenuated using extended-release formulations (venlafaxine XR), but different compounds can solve the problem, too. It would thus be desirable to find a compound with the advantages of venlafaxine while avoiding its disadvantages.
- Prodrugs have an identical pharmacological profile, but a more favourable pharmacokinetic profile.
- venlafaxine-N-oxide and O-desmethylvenlafaxine-N-oxide act as prodrugs: they are rapidly converted to their parent compounds venlafaxine and O-desmethyl- venlafaxine respectively.
- the invention relates to N-oxides having formula (1 ):
- the N-oxides of the invention may be substantially free of venlafaxine and O-desmethylvenlafaxine, and tautomers, stereoisomers, salts, hydrates and solvates thereof.
- Venlafaxine N-oxide and O-des-methylvenlafaxine N-oxide can be prepared by oxidizing venlafaxine or O-desmethylvenlafaxine with a suitable oxidizing agent, for instance with m-CPBA.
- the invention relates to racemates, mixtures of diastereomers and the individual stereoisomers of the N-oxides of the invention, as well as to hydrates and solvates thereof.
- the invention particularly relates to N-oxides having formula (1 ) wherein R 1 is CH 3 .
- Yet other preferred embodiments are (S)- and (R)-enantiomers of N-oxides having formula (1 ).
- Venlafaxine-N-oxide and compositions comprising them are useful in treating affections or diseases effectively treatable — albeit with side effects — with venlafaxine: depression, including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a. 'hot flashes'.
- the invention also comprises: pharmaceutical compositions for treating, for example, a disorder or condition treatable by venlafaxine, the compositions comprising an N-oxide of formula (1 ), and a pharmaceutically acceptable carrier; methods of treating a disorder or condition treatable by venlafaxine, the methods comprising administering to a mammal in need of such treating an N-oxide of formula (1 ); methods of treating a disorder or condition treatable by venlafaxine, the methods comprising administering to a mammal in need of such treating an N-oxide of formula (1 ); pharmaceutical compositions for treating a disorder or condition treatable by venlafaxine, the compositions comprising an N-oxide of formula (1 ), and a pharmaceutically acceptable carrier; methods for treating a disorder or condition treatable by venlafaxine, the methods comprising administering to a patient in need of such treating an N-oxide of formula (1 ).
- the invention also provides the use of an N-oxide of formula (1 ), for the manufacture of medicament.
- the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for instance venlafaxine or O-desmethyl-venlafaxine, for treating one or more of the conditions listed.
- another therapeutic agent or agents for instance venlafaxine or O-desmethyl-venlafaxine
- Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.
- the invention also provides compounds, pharmaceutical compositions, kits and methods for treating a disorder or condition treatable by venlafaxine, the method comprising administering to a patient in need of such treating an N-oxide of formula (1 ).
- the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
- the compounds of the present invention contain an asymmetric center. This will produce two optical isomers. All of the possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention.
- the present invention comprehends all such isomeric forms of these compounds.
- Formula (1 ) shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these diastereomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
- Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
- racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases: Methods well-known in the art.
- any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
- Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
- some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
- N-oxides of formula (1 ) detectable by PET or SPECT, also fall within the scope of the invention.
- compounds of the present invention may be provided substantially free of parent compound 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, venlafaxine, or O-desmethylvenlafaxine.
- substantially free is meant that compound of the present invention contains less than about 50%, 40%, 30%, 20%, 10%, 1 %, 0.5% or is, within detectable limits, free of venlafaxine or O-desmethylvenlafaxine as an impurity.
- Pharmaceutical compositions containing N-oxides of venlafaxine and/or O-desmethylvenlafaxine which are substantially free of venlafaxine and/or O-desmethylvenlafaxine are envisioned in accordance with the present invention.
- venlafaxine means the racemic compound (R,S)-1-[2-
- any compound metabolized in vivo to provide the bioactive agent i.e., the compound of formula (1 )
- Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites.
- the term "administering" shall encompass treating the various disorders described with the compound specifically disclosed, or with a compound that not specifically disclosed, but that converts to the specified compound in vivo after administration to the patient.
- Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule.
- Prodrugs i.e. compounds that when administered to humans by any known route, are metabolised to compounds having formula (1 ), belong to the invention.
- this relates to the hydroxy group, which can be reacted with organic acids to yield compounds having formula (1 ) wherein an additional group is present that is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
- an additional group is present that is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
- polymorphism is defined as the ability of a compound to exist in more than one crystal form, a so-called polymorph. Polymorphism is a frequently occurring phenomenon. Polymorphism is affected by several crystallization conditions such as temperature, level of supersaturation, the presence of impurities, polarity of solvent, rate of cooling. Polymorphs can be characterized by several methods such as solid state NMR, solubility tests, DSC or melting point determination, IR or Raman spectroscopy.
- composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
- this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- the term 'combination preparation' comprises both true combinations, meaning an N-oxide of formula (1 ), and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising an N-oxide of formula (1 ), and venlafaxine or another medicament in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
- the pharmacotherapy by definition is simultaneous.
- the contents of 'kit-of- parts' can be administered either simultaneously or at different time intervals.
- Treatment being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Dose recommended treatment dose is the same as for venlafaxine: 75 mg per day, administered in two or three divided doses, taken with food. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value.
- the dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
- the dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
- the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In general, oral and parenteral dosages will be in the range of 0.1 to 1 ,000 mg per day of total active ingredients.
- terapéuticaally effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic, preventative or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating or preventing the conditions listed herein.
- the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
- treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) preventing the disease or condition from occurring in a subject predisposed to the disease, but not yet diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing the condition to regress, or (4) stopping the symptoms of the disease.
- the term “medical therapy” intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- Nuclear magnetic resonance spectra ( 1 H NMR and 13 C NMR, APT) were determined in the indicated solvent using a Bruker DRX 600 ( 1 H: 600 MHz, 13 C: 150 MHz) at 300 K, unless indicated otherwise. The spectra were determined in deuterated DMSO, obtained from Cambridge Isotope Laboratories Ltd. Chemical shifts ( ⁇ ) are given in ppm downfield from tetramethylsilane ( 1 H). Coupling constants J are given in Hz.
- Peakshapes in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double quartet), T (triplet), 'dt' (double triplet), 'd' (doublet), 'dd' (double doublet), 's' (singlet), 'bs' (broad singlet) and 'rr ⁇ (multiplet).
- NH and OH signals were identified after mixing the sample with a drop of D 2 O.
- Flash chromatography refers to purification using the indicated eluent and silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm).
- Reactions were monitored by using thin-layer chromatography (TLC) on silica coated plastic sheets (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualised by UV light (254 nm) or I 2 .
- TLC thin-layer chromatography
- LC-MS Liquid Chromatography- Mass Spectrometry
- step total time flow ( ⁇ l/min) A(%) B(° ⁇
- the auto sampler has a 2 ⁇ l injection loop.
- the auto sampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 ⁇ m particles.
- the column is thermo stated in a Perkin Elmer series 200 column oven at 40° C.
- the column is connected to a Perkin Elmer series 200 UV meter with a 2.7 ⁇ l flowcel.
- the wavelength is set to 254 nm.
- the UV meter is connected to a Sciex API 150EX mass spectrometer.
- the mass spectrometer has the following parameters: Scanrange: 150-900 a.m.u.; polarity: positive; scan mode: profile ; resolution Q1 : UNIT ; step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.
- the light scattering detector is connected to the Sciex API 150.
- the light scattering detector is a Sedere Sedex 55 operating at 50° C and 3 bar N 2 .
- the complete system is controlled by a G3 powermac. Venlafaxine and its N-oxide were analyzed in mouse plasma and brain samples using a generic bioanalytical method comprising protein precipitation and HPLC with MS/MS detection.
- Proteins in 100 ⁇ l plasma were precipitated with acetonitrile, and 5 ⁇ l samples of the obtained solutions were analyzed. Complete brains were homogenized and centrifuged, and 10 ⁇ l samples of the supernatant were analyzed.
- LC-MS/MS Liquid Chromatography - Tandem Mass Spectrometry
- LC-MS/MS system performance was monitored using a reference solution injected at standard intervals. The method was not validated in detail, therefore the reported concentrations were good estimations.
- the Lower Limit Of Quantification (LLOQ) was established at 1.00 ng/ml and 5.00 ng/brain, for plasma and brain samples, respectively. Values below the LLOQ were given as best estimate.
- Reversed phase HPLC was performed using gradient elution by a Hypersil BDS C18 100 x 4.6 mm 3 ⁇ m analytical column, at 45 0 C and with a flow of 1.00 ml/min:
- Venlafaxine (0.28 g, 1.02 mmol) was dissolved in 20 ml DCM and cooled to -1 O 0 C. To the reaction mixture was added meta-chloroperbenzoic acid (m-CPBA, 0.8 g, 2.02 mmol) and the solution was stirred at -1 O 0 C for 30 minutes. Solid K 2 CO3 (2 g) was added and the resulting mixture was stirred for another 30 minutes at O 0 C. The reaction mixture was filtrated (glass funnel), and the precipitate was washed carefully with DCM.
- m-CPBA meta-chloroperbenzoic acid
- This material (23.8 g, mainly compound 11 ) was suspended in diethyl ether (500 ml.) and treated with lithium aluminum hydride (3.8g, 0.1 mol). The suspension was stirred for 18 h at rt. 5 N KOH (16 ml.) was added carefully, and the mixture was stirred for 15 min. Solids were removed by filtering over Celite, and washed (diethyl ether, 300 ml_). The filtrates were were dried (sodium sulfate) and concentrated. Yield: 21.4 g of compound 10 (60 %) as a white solid.
- S-Venlafaxine (i) The mother liquor of the resolution (see above) was freed by washing with 1 N NaOH (4 x 100 ml_), with water (3 x 200 ml.) and with brine (100 ml_). The organic phase was dried (sodium sulphate) and concentrated. Oil, solidifies quickly. This material was re-dissolved 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 started within 5 minutes. Ethyl acetate (50 ml.) was added and the mixture was stirred for 72 hours at room temperature.
- the mixture was stirred for 2 hours, while the temperature was allowed to raise to room temperature, and subsequently at reflux temperature for 16 hours.
- the reaction mixture was cooled to room temperature, poured into 2N HCI (cold, 300 mL) and stirred for 10 min.
- the aqueous phase was washed (ethyl acetate, 3 x 300 mL), then neutralized (pH 7) by means of slow (!) addition of NaHCO 3 (s), and extracted (ethyl acetate, 6 x 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 min.
- [ 3 H]-Serotonine uptake was stopped by filtration with a harvester and the non-incorporated radioactivity was removed by extensive washing. Filterplates with synaptosomes were dehydrated, and the amount of [ 3 H]-serotonin present was determined by Betaplate liquid scintillation counting. Inhibitory effects on the uptake of the [ 3 H]-serotonin were expressed as plC 5 o value, that is the negative logarithm of the concentration at which half maximal inhibition of radiolabeled neurotransmitter uptake is achieved. plC 50 values given are mean values of 2-9 experiments performed in duplicate. Testcompounds, 10 "2 M dissolved in DMSO, were diluted in Krebs Ringer buffer to the testconcentrations of 10 "8 to 10 "5 M. Further experimental details were as described ⁇ Coyle, 1969).
- [ 3 H]- Norepinephrine uptake was stopped by filtration with a harvester and the non-incorporated radioactivity was removed by an extensive washing programme.
- the filterplates with synaptosomes were dehydrated and the amount of [ 3 H]- norepinephrine present was determined by Betaplate liquid scintillation counting.
- Inhibitory effects on the uptake of the [ 3 H]- norepinephrine were expressed as plC 50 value, that is the negative logarithm of the concentration at which half maximal inhibition of radiolabeled neurotransmitter uptake is achieved.
- plC 50 values given are mean values of 2-9 experiments performed in duplicate. Testcompounds, 10 "2 M dissolved in DMSO, were diluted in Krebs Ringer buffer to testconcentrations of 10 "8 - 10 "5 M. Further experimental details were as described (Coyle, 1969).
- [ 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 determined by Betaplate liquid scintillation counting. Compounds were tested in a concentration range of 10 "9 to 10 "5 M. Inhibitory effects on the uptake of [ 3 H]-dopamine were expressed using the plC 50 value (the negative logarithm of the concentration at which the drug caused 50% uptake inhibition). Inhibition of DA uptake was performed in duplicate.
- the human colon model TIM2 (TNO Intestinal Model 2): is a dynamic model for the human large intestine that simulates in vivo conditions. It is an artificial digestive system that has been validated by many studies (Minekus, 1999).
- Venlafaxine-N-oxides are prodrugs of the parent compound. They are useful in the treatment of diseases effectively treatable — albeit with side effects — with venlafaxine: depression, including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a. 'hot flashes'.
- depression including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a. 'hot flashes'.
- EXAMPLE 4 PHARMACOKINETIC AND PHARMACOLOGICAL TESTRESULTS
- venlafaxine In mice, venlafaxine is only marginally metabolized to its N-oxide: The concentration thereof in the plasma never exceeds 1 - 2% of that of the parent compound, and in brain only traces can be found. When venlafaxine-N-oxide itself is administered it is reduced to the parent compound. Approximately one hour after i.v. administration of venlafaxine-N-oxide, venlafaxine concentrations in plasma and brain exceed those of the N-oxide. The effects are more pronounced after oral administration: Venlafaxine concentrations in both plasma and brain rise to levels that are a factor 10 to 100 higher than those of the N-oxide.
- venlafaxine-N-oxide 1 mg was inserted into the lumen (120 ml) of the TIM2 model (see above, Minekus, 1999). Samples from the lumen and the dialysate (the latter being a model for the vascular bed of the intestines) were taken at various time intervals, and analyzed for venlafaxine-N-oxide and venlafaxine: Table 2:
- N-oxides of formula (1 ) are formulated into pharmaceutical compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein.
- Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a person skilled in the art from the specification and general knowledge in the art.
- the active ingredient for instance, may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
- compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
- the pharmaceutical formulation contains at least one N-oxide of formula (1 ) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier.
- the total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w). In some embodiments, the amount of active ingredient is greater than about 95% (w/w) or less than about 0.1% (w/w).
- the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- the mixture may then be processed into granules or pressed into tablets.
- a tablet is prepared using the ingredients below: Ingredient Quantity (mg/tablet) venlafaxine N-oxide 10
- the components are blended and compressed to form tablets each weighing 230 mg.
- the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
- the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
- Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
- Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
- solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent.
- solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
- formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
- container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
- formulations of the present invention in the manufacture of medicaments for use in treating depression, including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a.
- 'hot flashes' and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one N-oxide of formula (1 ), either as such or, in the case of prodrugs, after administration, to a patient suffering from depression, including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a. 'hot flashes'.
- major depressive disorder generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, panic disorder, general depressive disorders, diabetic neuropathy, migraine and vasomotor symptoms associated with menopause, a.k.a. 'hot flashes'.
- several pharmaceutical compositions are given, comprising preferred active compounds for systemic use or topical application. Other compounds of the invention or combinations thereof, may be used in place of (or in addition to) said compounds.
- concentration of the active ingredient may be varied over
- Ettmayer P. et ai, "Lessons learned from marketed and investigational prodrugs", J.Med.Chem., 47, 2393-2404, 2004.
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- Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2699961A CA2699961A1 (en) | 2007-06-26 | 2008-06-23 | N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs |
EA201070055A EA201070055A1 (en) | 2007-06-26 | 2008-06-23 | N-OXIDES OF VENLAFAXIN AND O-DESMETHYL VENLAFAXIN AS PROCEDURES |
JP2010513873A JP2010531326A (en) | 2007-06-26 | 2008-06-23 | N-oxide of venlafaxine and O-desmethylvenlafaxine as prodrugs |
CN2008800220292A CN101939293A (en) | 2007-06-26 | 2008-06-23 | As the Venlafaxine of prodrug and the N-oxide compound of O-ODV |
BRPI0813658A BRPI0813658A2 (en) | 2007-06-26 | 2008-06-23 | compound, medicament, pharmaceutical composition, combined pharmaceutical preparation, uses of a compound and a combined preparation, and process for the preparation of compound. |
EP08774213A EP2170816A1 (en) | 2007-06-26 | 2008-06-23 | N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs |
AU2008267273A AU2008267273A1 (en) | 2007-06-26 | 2008-06-23 | N-oxides of venlafaxine and O-desmethylvenlafaxine as prodrugs |
IL202464A IL202464A0 (en) | 2007-06-26 | 2009-12-02 | N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US94620007P | 2007-06-26 | 2007-06-26 | |
EP07111028 | 2007-06-26 | ||
US60/946,200 | 2007-06-26 | ||
EP07111028.2 | 2007-06-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009000797A1 true WO2009000797A1 (en) | 2008-12-31 |
Family
ID=39733771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/057939 WO2009000797A1 (en) | 2007-06-26 | 2008-06-23 | N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP2170816A1 (en) |
KR (1) | KR20100040881A (en) |
AU (1) | AU2008267273A1 (en) |
CA (1) | CA2699961A1 (en) |
EA (1) | EA201070055A1 (en) |
IL (1) | IL202464A0 (en) |
WO (1) | WO2009000797A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011157727A2 (en) | 2010-06-15 | 2011-12-22 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Method for preparing a composite material comprising a polymer matrix and a filler consisting of inorganic ion-exchange particles |
US11473878B2 (en) | 2020-10-28 | 2022-10-18 | Doron LABOCK | Arrangement for ballistically protecting a driver or passenger in a civilian vehicle |
Citations (3)
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US4535186A (en) * | 1983-04-19 | 1985-08-13 | American Home Products Corporation | 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives |
EP0532348A2 (en) * | 1991-09-13 | 1993-03-17 | Mcneilab, Inc. | A tramadol N-oxide material, enantiomers and compositions thereof, and their use |
EP1721889A1 (en) * | 2005-05-12 | 2006-11-15 | Dishman Pharmaceuticals & Chemicals Ltd. | Process for the preparation of phenethylamine derivatives |
-
2008
- 2008-06-23 EA EA201070055A patent/EA201070055A1/en unknown
- 2008-06-23 AU AU2008267273A patent/AU2008267273A1/en not_active Abandoned
- 2008-06-23 KR KR1020107001829A patent/KR20100040881A/en not_active Application Discontinuation
- 2008-06-23 WO PCT/EP2008/057939 patent/WO2009000797A1/en active Application Filing
- 2008-06-23 EP EP08774213A patent/EP2170816A1/en not_active Withdrawn
- 2008-06-23 CA CA2699961A patent/CA2699961A1/en not_active Abandoned
-
2009
- 2009-12-02 IL IL202464A patent/IL202464A0/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4535186A (en) * | 1983-04-19 | 1985-08-13 | American Home Products Corporation | 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives |
EP0532348A2 (en) * | 1991-09-13 | 1993-03-17 | Mcneilab, Inc. | A tramadol N-oxide material, enantiomers and compositions thereof, and their use |
EP1721889A1 (en) * | 2005-05-12 | 2006-11-15 | Dishman Pharmaceuticals & Chemicals Ltd. | Process for the preparation of phenethylamine derivatives |
Non-Patent Citations (1)
Title |
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BICKEL M H: "THE PHARMACOLOGY AND BIOCHEMISTRY OF N-OXIDES", 1969, PHARMACOLOGICAL REVIEWS, WILLIAMS AND WILKINS INC., BALTIMORE, MD,, US, PAGE(S) 325-355, ISSN: 0031-6997, XP000984853 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011157727A2 (en) | 2010-06-15 | 2011-12-22 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Method for preparing a composite material comprising a polymer matrix and a filler consisting of inorganic ion-exchange particles |
US11473878B2 (en) | 2020-10-28 | 2022-10-18 | Doron LABOCK | Arrangement for ballistically protecting a driver or passenger in a civilian vehicle |
Also Published As
Publication number | Publication date |
---|---|
EA201070055A1 (en) | 2010-06-30 |
IL202464A0 (en) | 2010-06-30 |
AU2008267273A1 (en) | 2008-12-31 |
EP2170816A1 (en) | 2010-04-07 |
KR20100040881A (en) | 2010-04-21 |
CA2699961A1 (en) | 2008-12-31 |
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