CN101939293A - As the Venlafaxine of prodrug and the N-oxide compound of O-ODV - Google Patents
As the Venlafaxine of prodrug and the N-oxide compound of O-ODV Download PDFInfo
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- CN101939293A CN101939293A CN2008800220292A CN200880022029A CN101939293A CN 101939293 A CN101939293 A CN 101939293A CN 2008800220292 A CN2008800220292 A CN 2008800220292A CN 200880022029 A CN200880022029 A CN 200880022029A CN 101939293 A CN101939293 A CN 101939293A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The present invention relates to respectively as Venlafaxine-N-oxide compound and O-ODV-N-oxide compound, the pharmaceutical composition that comprise these N-oxide compounds, their preparation method and the preparation of compositions method of Venlafaxine with the prodrug of its main (activity) metabolite O-ODV.The present invention relates to the to have general formula N-oxide compound of (1),
R wherein
1Be H or CH
3And their tautomer, steric isomer, hydrate and solvate.The invention still further relates to the purposes of this N-oxide compound and composition, in particular for making the purposes of medicament, this medicament can be used for treating illness or the disease that available Venlafaxine is effectively treated (even side effect is arranged).
Description
Technical field
The present invention relates to medicine and organic chemistry filed, and the have general formula Venlafaxine-N-oxide compound and the O-ODV-N-oxide compound of (1) be provided:
Asterisk (*) mark unsymmetrical carbon wherein, R
1Be H or CH
3With their tautomer, steric isomer, hydrate and solvate, respectively as the prodrug of Venlafaxine with its main (activity) metabolite O-ODV, and the pharmaceutical composition that comprises this compound, the preparation method of this compound and preparation of compositions method.
Background technology
Venlafaxine is the phenylethylamine bicyclic derivatives, and is chemically irrelevant with three rings, Fourth Ring or other available antidepressive.It is reported that its (-)-enantiomorph is the more potent inhibitor of norepinephrine synaptosome picked-up, and its (+)-enantiomorph is suppressing to have more selectivity (Howell, 1994) aspect the serotonin picked-up.Venlafaxine is as the racemic modification list marketing.
(±)-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl]-hexalin, Venlafaxine
(U.S. Patent number 4,761,501; Pento, 1988)
The mechanism of the antidepressant effect of the Venlafaxine in the mankind is considered to and the active strong correlation that adds of its neurotransmitter in CNS.Preclinical study has shown that Venlafaxine and its major metabolite O-ODV are the potent inhibitor of neurone serotonin and norepinephrine reuptake and the weak inhibitor of dopamine reuptake.O-demethyl-Venlafaxine is unique main active metabolite.Other metabolite is the N-ODV, and N, O-dinor-Venlafaxine (Klamerus, 1992).Succsinic acid O-ODV is in the later stage of its exploitation, and received recently that FDA sends be used for the treatment of the hypochondriacal letter of ratifying of severe.This compound is also being developed the therapeutant that becomes the vasomotor symptoms relevant with menopause.
The N-oxide compound is just known since 1894.The present consistent N-of the generally acknowledging oxide compound metabolite that is many tertiary amines, and in most of the cases also be intermediate between tertiary amine and their the N-alkylation removal analogue.Great majority, but not all tertiary amine medicine produces the N-oxide compound.For example morphine, imipramine, promazine, CN and nicotine are exactly this situation.The N-oxidation take place what from trace to changing near Quantitative yield.Some N-oxide compounds show more potent than their corresponding tertiary amine.The most famous example is a zeisin in them
One of the most frequently used medicine in psychosis and general medical science.Yet, more often than not, find that the N-oxide compound is more weak than their corresponding tertiary amine effects, and the most common metabolism inactivation that is considered to of N-oxidation.Though can easily the N-oxide compound be reduced into the tertiary amine of their correspondences by chemical mode, this takes place with different degree in human body.Some N-oxide compounds can experience almost quantitative reduction and transform, and become corresponding tertiary amine and in other cases, conversion is the only reaction of trace, perhaps even fully do not have (Bickel, 1969).Therefore, the formation of N-oxide compound and their corresponding tertiary amine is unpredictable.In case form, the N-oxide compound may more have activity than their corresponding tertiary amine, poorer or even the complete non-activity of activity.The N-oxide compound can be reduced into corresponding tertiary amine or cannot.When they can the time, this reaction may only be a trace or near quantitative.
Since Paracelsus (' Sola dosis facit venenum '), generally accepted is that the treatment and the toxic action of medicine is relevant in the concentration of relevant target site with them.Because generally speaking, the latter is not easy to obtain, so blood plasma level is as the approximation of related drugs concentration.During drug development, the plasma concentration window that definition is fit to, thus the lower limit of effect or lower bound and the side effect tangible upper bound that begins to become is provided.Under ideal state, these two kinds of concentration differences are apart from effective to show so greatly, yet the method drug administration that does not have side effects is easy.In fact, situation may be an ideal hardly always, and most drug shows side effect.In most of the cases, the generation of side effect may have relation with peak plasma concentrations, and this peak plasma concentrations surpasses and the relevant threshold level of side effect generation.Venlafaxine produces the peak plasma concentrations that causes side effect.With use Venlafaxine relevant and the patient of placebo treatment (promptly, the incidence of Venlafaxine is 2 times of placebo at least) in not with equate modal adverse events (incidence is 5% or bigger) that incidence is observed comprise lasting hypertension, headache, unable, sweat, feel sick, constipation, somnolence, dry mouth, dizzy, insomnia, nervous, worried, fuzzy or unclear vision, and abnormal ejaculation/orgasm of the male sex or impotence (Physicians ' Desk Reference, 1999; Sinclair, 1998).These undesirable actions are dosage level, frequency and the extended period of limit drug therapy significantly.Can use prolongation-delivery formulations (Venlafaxine XR) to weaken adverse events, but different compounds also can address this problem.Therefore it will be desirable finding the advantage with Venlafaxine to avoid the compound of its shortcoming simultaneously.Prodrug has identical pharmacological characteristics, but has more favourable pharmacokinetic properties.
Summary of the invention
When oral administration, Venlafaxine-N-oxide compound and O-ODV-N-oxide compound serve as prodrug: they promptly are transformed into their parent compound Venlafaxine and O-demethyl-Venlafaxine respectively.The present invention relates to the to have general formula N-oxide compound of (1):
Asterisk (*) mark unsymmetrical carbon wherein, R
1Be H or CH
3And their tautomer, steric isomer, hydrate and solvate.N-oxide compound of the present invention can be substantially free of Venlafaxine and O-ODV and their tautomer, steric isomer, salt, hydrate and solvate.Venlafaxine N-oxide compound and O-ODV N-oxide compound can be by using the oxygenant that is fit to, and for example m-CPBA oxidation Venlafaxine or O-ODV prepare.The present invention relates to the racemic modification of N-oxide compound of the present invention, the mixture of diastereomer and independent steric isomer, with and hydrate and solvate.
The invention particularly relates to the have general formula wherein R of (1)
1Be CH
3The N-oxide compound.
Another preferred embodiment of the present invention is the wherein R with general formula (1)
1It is the N-oxide compound of H.
Other embodiment preferred that also has is (S) with N-oxide compound of general formula (1)-and (R)-enantiomer.
Venlafaxine-N-oxide compound can be used for treating illness or the disease that available Venlafaxine is effectively treated (even side effect is arranged) with the composition that comprises them: the dysthymia disorders, generalized-anxiety disorder, obsessional idea that comprises major depressive disorder and behavior disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and with menopause relevant vasomotor symptoms, also be called ' hot flush '.
The present invention also comprises:
For example be used for the treatment of, can be by the obstacle of Venlafaxine treatment or the pharmaceutical composition of situation, said composition comprises acceptable carrier in the N-oxide compound of general formula (1) and the pharmacy;
Treatment can be by the obstacle of Venlafaxine treatment or the method for situation, and this method comprises the N-oxide compound to the administration general formula (1) of this kind of needs treatment;
Treatment can be by the obstacle of Venlafaxine treatment or the method for situation, and this method comprises the N-oxide compound to the administration general formula (1) of this kind of needs treatment;
Being used for the treatment of can be by the obstacle of Venlafaxine treatment or the pharmaceutical composition of situation, and said composition comprises acceptable carrier in the N-oxide compound of general formula (1) and the pharmacy;
Treatment can be by the obstacle of Venlafaxine treatment or the method for situation, and this method comprises the N-oxide compound of the patient of this kind of needs treatment being used general formula (1);
The present invention also provides the N-oxide compound of general formula (1) to be used to make the purposes of medicament.
The invention further relates to combined therapy, wherein with compound of the present invention, or comprise the pharmaceutical composition of The compounds of this invention or preparation simultaneously use successively or as with another kind of therapeutical agent (or several therapeutical agent) for example the combination preparation of Venlafaxine or O-demethyl-Venlafaxine use, be used for the treatment of one or more listed situations.This type of other therapeutical agent can be before using The compounds of this invention, simultaneously or use afterwards.
The present invention also is provided for treating can be by the obstacle of Venlafaxine treatment or compound, pharmaceutical composition, kit (kit) and the method for situation, and this method comprises the N-oxide compound of the patient of this kind of needs treatment being used general formula (1).
The present invention also provides the intermediate that uses in the preparation method of The compounds of this invention and those methods.
The compounds of this invention comprises asymmetric center.This will produce two kinds of optically active isomers.All possible optically active isomer and diastereomer (with mixture and pure compound or partially purified compound form) belong to the present invention.All these isomeric forms of these compounds are contained in the present invention.General formula (1) is represented the preferred stereochemical structure that do not have of this compounds.These diastereomers independently synthetic or their chromatographic separation can realize by suitable modification method disclosed herein like that by as known in the art.Can measure their absolute stereo chemistry by the X-radiocrystallography of crystallized product or crystallization of intermediate, in the time of if necessary, described crystallized product or crystallization of intermediate adopt the reagent of the asymmetric center that comprises known absolute configuration to derive.Can the racemic mixture of compound be separated into each enantiomer by method well known in the art, for example the racemic mixture of compound is coupled on the compound of enantiomer-pure to form non-enantiomer mixture, then by standard method, for example fractional crystallization or chromatography are with individual diastereomeric separation.The cracking that can pass through the chirality residue that added then is transformed into pure enantiomer with this diastereomer derivative.Can also pass through chromatography, utilize chiral stationary phase directly the racemic mixture of this compound to be separated: method well known in the art.Perhaps, can be synthetic by stereoselectivity, use optical purity raw material or reagent with configuration known, by method well known in the art, obtain any enantiomer of compound.
Some crystal formations of compound can be used as pleomorph and exist: think that itself belongs to the present invention.In addition, some compounds can with water (being hydrate), or organic solvent commonly used forms solvate.This type of solvate also belongs to the scope of the invention.
The N-oxide compound of isotope-labeled general formula (1) (can detect by PET or SPECT) also belongs to the scope of the invention.The same applies to usefulness [
13C]-, [
14C]-, [
3H]-, [
18F]-, [
125I]-or be suitable for the N-oxide compound of general formula (1) of atom mark of other isotopic enrichment of receptors bind or metabolism research.
The N-oxide compound of finding Venlafaxine and O-ODV can be used as they separately the incident of the prodrug of parent compound provide and used the possibility of these compounds as alternatives, described alternatives has the acting duration of prolongation and the clinical benefit of the peak plasma concentrations that weakens, thereby causes the side effect profile improved.Therefore, in some embodiments of the present invention, can provide compound of the present invention, it is substantially free of parent compound 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl]-hexalin, Venlafaxine, or O-ODV.So-called being substantially free of is meant that compound of the present invention comprises less than about 50%, 40%, 30%, 20%, 10%, 1%, 0.5% Venlafaxine or O-ODV or do not contain Venlafaxine or O-ODV as impurity in limit of detection.According to the present invention, conceived the pharmaceutical composition of the N-oxide compound (being substantially free of Venlafaxine and/or O-ODV) that comprises Venlafaxine and/or O-ODV.
Definition
Term as used herein " Venlafaxine " be meant racemic compound (R, S)-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin.
Metabolism and any compound of biologically active agent (being the compound of general formula (1)) is provided is prodrugs in the application's scope and spirit in vivo.Prodrug is a therapeutical agent, itself is inactive, but is transformed into one or more active metabolites.Therefore, in methods of treatment of the present invention, term administering or give " should comprise with disclosed especially compound, or open especially but after being administered to the patient, be transformed into the described various obstacles of compounds for treating of appointed compound in vivo.Prodrug is the biological reversible derivatization thing of drug molecule, and it is used for overcoming some obstacles that application parent drug molecule is run into.These obstacles include but not limited to, metabolism and target restriction (Bundgaard, 1985 before solvability, perviousness, stability, the body circulation; King, 1994; Stella, 2004; Ettmayer, 2004;
2005).Prodrug promptly is metabolised to when being administered to the mankind by any known approach and has general formula the compound of compound of (1) belongs to the present invention.Specifically, this relates to hydroxyl, it can react with organic acid and produce the have general formula compound of (1), wherein exist in the additional group of removing easily after using, for example, but be not limited to amidine, enamine, Mannich base, hydroxyl-methylene derivatives, O-(acyloxy methene amido manthanoate) derivative, carbamate, ester, acid amides or enamine ketone.
Term " polymorphism " is defined as the ability of compound to exist more than a kind of crystalline form (so-called polymorphic).Polymorphism is the phenomenon that takes place usually.Polymorphism is subjected to some crystallization conditions, and for example temperature, supersaturation level, the existence of impurity, polarity of solvent, rate of cooling influence.Polymorphic can pass through for example solid state NMR, solubility test, DSC or fusing point test of several methods, IR or Raman spectroscopy and characterize.
For simpler and clearer description is provided, some quantitative expressions term of no use " approximately " restriction that this paper provides.It should be understood that, no matter whether clearly use term " approximately ", each amount that this paper provides means the actual value that provides, and mean the approximation of the value that so provides, this approximation can reasonably be derived based on the ordinary skill of this area, comprises by so test of the value of providing and/or the approximation that measuring condition draws.In the whole description and claim of this specification sheets, word " comprise " and the modified example of this word as " comprising " with do not get rid of " comprising " intention of other additive, component, integer or step.Term as used herein " composition " contains predetermined amounts or ratio comprises the product of specifying composition, and by pressing the spawn that the specified amount combination specifies composition directly or indirectly to obtain.As for pharmaceutical composition, the product that comprises one or more activeconstituentss and contain the optional carrier of inert fraction contained in this term, and by combination, complexing or assemble any two or more compositions, or by one or more compositions that dissociate, or by the reaction of other type of one or more compositions or the spawn that interacts and directly or indirectly obtain.Generally speaking, be prepared as follows pharmaceutical composition: activeconstituents evenly and is closely associated with liquid vehicle or fine powder crushed solid carrier or both, then if necessary, this product is shaped as required preparation.Pharmaceutical composition comprises that enough active target compound is with to producing desired result after the process of disease or the situation.Therefore, pharmaceutical composition of the present invention is contained by any composition with acceptable carrier fusion preparation in The compounds of this invention and the pharmacy.
In the application's context, term ' combination preparation ' had both comprised true combination, promptly physically be combined in the N-oxide compound of the general formula (1) in a kind of formulation example such as tablet or the injection liquid, with other medicament, comprise ' kit box (kit-of-parts) ' again, it is included in the N-oxide compound of the general formula (1) in the individually dosed form, with Venlafaxine or another kind of medicament, and working instructions, randomly also have the instrument of being convenient to use the conformability component composition, for example label or figure.Adopt true combination, according to definition, pharmacological agent takes place simultaneously.The content of ' kit box ' can be used simultaneously or with different time at interval.Treatment will be depended on the feature of employed other medicament simultaneously or sequentially, beginning and the time length of feature as acting on, and blood plasma level, clearance rate etc., and depend on disease, the feature of its stage and individual patient.
" acceptable in the pharmacy " means carrier, thinner or vehicle must can be compatible with other composition of preparation and harmless to its recipient.
Dosage: the treatment dose of recommendation is identical with Venlafaxine: 75mg/ days, use by two or three divided doses with food.Pharmacokinetics, pharmacodynamics and other consideration can be with the actual DM of using to higher or lower values.The dosage of the compound that is applied will depend on patient's relevant indication, age, body weight and sex and can determine by the doctor.This dosage will be preferably 0.01mg/kg-10mg/kg.The typical per daily dose of activeconstituents changes in wide region and will depend on various factors for example patient's relevant indication, route of administration, age, body weight and sex, and can be determined by the doctor.Generally speaking, oral and parenteral dosage will be 0.1-1,000mg/ days gross activity compositions.
Term as used herein " significant quantity in the treatment " is meant the amount of the situation that therapeutical agent treatment or prevention can be by using present composition treatment.This amount is the amount that is enough in tissue system, animal or human's class to show detectable treatment, the preventative or property improved response.This effect for example can comprise, the situation that treatment or prevention this paper list.Curee's accurate significant quantity will depend on this curee the size and healthy, the nature and extent of the situation of being treated, treatment doctor's (researchist, animal doctor, medical doctor or other clinician) recommendation and for to use the therapeutics of selection, or the combination of therapeutics.Therefore, it is useless specifying accurate significant quantity in advance.
Term as used herein " treatment " is meant Mammals, preferred human situation or any processing of disease, and comprise: (1) wards off disease or situation takes place easily suffering from this disease but do not make a definite diagnosis among the curee who suffers from this disease, (2) suppress disease or situation, promptly stop its development, (3) palliate a disease or situation, promptly cause this situation to disappear, or (4) stop the symptom of disease.Term as used herein " therapeutic treatment " is intended to comprise to human or other Mammals in vivo or preventative, the diagnostic and the therapeutic scheme that exsomatize and carry out.Term as used herein " curee " is meant animal, and preferred mammal is most preferably human, and it is the target of treatment, observation or experiment.
Embodiment 1: analytical procedure
Except as otherwise noted, use Bruker DRX 600 (
1H:600MHz,
13C:150MHz), under 300K, in the solvent of pointing out, the mensuration NMR (Nuclear Magnetic Resonance) spectrum (
1H NMR and
13C NMR, APT).Among the deuterate DMSO that obtains from Cambridge Isotope Laboratories Ltd., measure spectrum.From tetramethylsilane (
1H) downfield provides chemical shift (δ) with ppm.Provide coupling constant J with Hz.Peak shape in the NMR spectrum is represented with symbol ' q ' (quartet), ' dq ' (two quartet), ' t ' (triplet), ' dt ' (two triplet), ' d ' (doublet), ' dd ' (two doublet), ' s ' (unimodal), ' bs ' (wide unimodal) and ' m ' (multiplet).With sample and a D
2After mixing, identifies O NH and OH signal.
On B ü chi B-545 melting point apparatus, write down fusing point.
Hurried chromatography is meant the purifying that uses specified eluent and silica gel (Acros:0.030-0.075mm or Merck silica gel 60:0.040-0.063mm).
Adopt specified eluent monitoring reaction by using tlc (TLC) to go up at the plastics sheet (Merck precoating silica gel 60F254) of silica-coating.By UV light (254nm) or I
2Make a video picture.
Use is carried out C/MS (liquid chromatography-mass spectrography) (LC-MS) by the system that 2 Perkin Elmer series 200 micropumps constitute.By the 50 μ l threeway mixing tanks that are connected with Gilson 215 automatic samplers pump is connected to each other.This method is as follows:
A=100% water and 0.025%HCOOH and 10mmol NH
4HCOO pH=+/-3
B=100%ACN and 0.025%HCOOH
This automatic sampler has 2 μ l injection ring.This automatic sampler with contain 3 μ m particulate Waters Atlantis C1830 * 4.6mm posts and be connected.Be in temperature constant state in the PerkinElmer series 200 post baking ovens of this post under 40 ℃.This post is connected with the Perkin Elmer series 200UV meter that contains 2.7 μ l flow cells (flowcel).Wavelength is set to 254nm.This UV meter is connected with Sciex API 150EX mass spectrograph.This mass spectrograph has following parameter:
Sweep limit: 150-900a.m.u.; Polarity: just; Scan pattern: curve; Resolving power Q1:UNIT; Step-length: 0.10a.m.u.; The time of each scanning: 0.500sec; NEB:10; CUR:10IS:5200; TEM:325; DF:30; FP:225 and EP:10.Light scattering detector is connected with Sciex API 150.Light scattering detector is at 50 ℃ and 3 crust N
2The Sedere Sedex 55 of following operation.By G3 powermac control total system.
Use comprises the general biological analytical procedure of protein precipitation and has the HPLC analysis mice plasma of MS/MS detection and Venlafaxine and its N-oxide compound in the brain sample.
With the protein of acetonitrile precipitation in 100 μ l blood plasma, and analyze 5 μ l samples of the solution obtained.With complete brain homogenizing and centrifugal, and analyze 10 μ l supernatant liquors.
Use Sciex API4000 LC-MS/MS to carry out liquid phase chromatography-polyphone mass spectroscopy (LC-MS/MS).Use the calibration sample (it is carried out the processing identical with study sample) that extracts in the scope of 1-5000ng/ml and 5.0-5000ng/ brain, to quantize sample respectively for blood plasma and brain sample.Use the compound peaks area to quantize.Working curve is fitted to model y=A+Bx+Cx
2(y is the peak area of analyte, and x is the nominal calibrated horizontal, and unit is ng/ml (blood plasma) or ng/g (brain), and A is an intercept, and B is a slope, and C is the description of curvature).Use 1/x
2Weighting.The reference solution monitoring LC-MS/MS system performance that use is injected in the normal space.At length do not verify this method, therefore the concentration of report is good estimated value.For blood plasma and brain sample, quantized lower limit (LLOQ) is set up at 1.00ng/ml and 5.00ng/ brain respectively.Provide value less than LLOQ as optimum estimation value.Use gradient elution,, carrying out reversed-phase HPLC under 45 ℃ and under the flow of 1.00ml/min by Hypersil BDS C18 100 * 4.6mm 3 μ m analytical columns:
| Solvent orange 2 A | 100mM?NH 4FA/1％FA |
| Solvent B | Milli-Q water |
| Solvent C | Methyl alcohol |
| Solvent D | Acetonitrile |
Use positive MRM ionization to carry out detection on MS/MS.The ion of measuring is:
Embodiment 2: specific compound synthetic
As described in EP 1 721 889, synthesize (R, S)-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl]-hexalin (Venlafaxine) and (R, S)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl) ethyl]-hexalin (O-ODV).The latter's replacement scheme is as follows.
(R, S)-1-[2-oxo bridge-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl]-hexalin (Venlafaxine N-oxide compound):
(0.28g 1.02mmol) is dissolved in 20ml DCM and be cooled to-10 ℃ with Venlafaxine.(m-CPBA, 0.8g 2.02mmol) and at-10 ℃ stirred this solution 30 minutes down to chloro peroxybenzoic acid between adding in this reaction mixture.Add solid K
2CO
3(2g) and in the mixture of 0 ℃ of following restir gained 30 minutes.Filter (glass funnel) this reaction mixture, and with DCM washing precipitation carefully.The solution that concentrates gained is also by hurried chromatography (SiO
2, DCM/MeOH (95/5 then 9/1)) carry out purifying and be produced as solid title compound (0.22g, 74%).mp?145℃.LCMS；R
t：1.12min，([M+H]
+＝294)。
1H-NMR(600MHz，D
6DMSO)：δ7.12(bd，J＝8Hz，2H)，6.86(bd，J＝8Hz，2H)，3.95-3.89(m，1H)，3.73(s，3H)，3.56-3.52(m，1H)，3.28-3.25(m，1H)，3.14(s，3H)，2.95(s，3H)，1.69-1.53(m，3H)，1.47-1.42(m，1H)，1.38-1.32(m，2H)，1.31-1.25(m，1H)，1.02(dt，J＝11Hz，4Hz，1H)，0.87(dt，J＝11Hz，4Hz，1H)，0.77-0.69(m，1H)。
Can prepare by identical method (R, S)-1-[2-oxo bridge-(dimethylamino)-1-(4-hydroxyphenyl) ethyl]-hexalin (O-ODV N-oxide compound).
As (S) of synthetic Venlafaxine as described in the following scheme-and (R)-enantiomer, their N-oxide compound and O-demethyl analogues separately.
(R, S)-1-(2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl)-hexalin (Venlafaxine, 10):
By add formaldehyde (37%, 41mL, 1.48mol) (33g, (99%, 54mL is 1.43mol) and in the water (330mL) 0.13mol) to be dissolved in formic acid with hexalin.This mixture 2h refluxes.Reaction mixture is concentrated to 150mL (pH value～1.0), and also (4 * 100mL) extract this mixture with ethyl acetate to add water (100ml).In ice bath, cool off this water layer and be basified to pH value～10 by adding 50%NaOH.(3 * 100mL) extract this mixture, use Na with ethyl acetate
2SO
4Dry and concentrated.Productive rate:
This material (23.8g mainly is a compound 11) is suspended in the ether (500mL) also with lithium aluminium hydride (3.8g, 0.1mol) processing.At room temperature stirred this suspension 18 hours.Add 5N KOH (16mL) carefully, and stirred this mixture 15 minutes.By solids removed by filtration on diatomite (Celite), and washing (ether, 300mL).Dry (sodium sulfate) filtrate also concentrates.Produce: 21.4g is the compound 10 (60%) of white solid.
1H-NMR(300MHz，CDCl
3)：δ7.05(d，2H，J＝8.8Hz)，6.81(d，2H，J＝8.8Hz)，3.79(s，3H)，3.27(t，1H，J＝12.6)，2.93(dd，1H，
2J＝3.2Hz，
3J＝12.5Hz)，2.32(s，6H)，2.30(dd，1H，
2J＝3.2Hz，
3J?12.5Hz)，1.82-1.61(m，3H)，1.60-1.45(m，3H)，1.42-1.22(m，2H)，1.01-0.78(m，2H)。
R-Venlafaxine (the above compound in the scheme 2):
Will (R, S)-(23.4g 84mmol) is dissolved in ethyl acetate (160mL) to Venlafaxine.In this solution, add D-dimethylbenzene acyl group tartrate (18.7g, 48mmol) solution in ethyl acetate (130mL).This salt begins precipitation in 10 minutes.At room temperature stirred this mixture 4 hours.By on glass filter, filtering collecting precipitation, and with ethyl acetate (2 * 100mL) washings.White crystalline solid.From ethyl acetate: methyl alcohol (6: 1,100mL) this solid of recrystallize.On glass filter, collect this solid.Output: 14.0g.With 2N NaOH (cold, 180mL) handle this material.With ethyl acetate (3 * 200mL) aqueous phase extracted.With 2N NaOH (cold, 75mL) wash this organic phase, wash this organic phase then with water, be neutral (pH value 7) up to washes.Dry (sodium sulfate) this organic phase also concentrates.Produce: 8.1g is the R-Venlafaxine (2) of white crystalline solid.m.p.：106℃-109.5℃。[α]
D 23＝-8.0(c＝1.5，MeOH)。Chirality HPLC:99% enantiomeric excess (e.e).
1H-NMR (CDCl
3): referring to above.
S-Venlafaxine (1):
By with 1N NaOH (4 * 100mL), water (3 * 200mL) and the mother liquor of salt solution (100mL) the washing described fractionation of release (referring to above).Dry (sodium sulfate) this organic phase also concentrates.Oil is promptly fixed.This material is dissolved in ethyl acetate (75mL) again.Add L-dimethylbenzene acyl group tartrate (11.3g, 29mmol) solution in ethyl acetate (75mL).In 5 minutes, begin precipitation.Add ethyl acetate (50mL) and at room temperature stirred this mixture 72 hours.On glass filter, collect solid.Output: 14.2g.With 2NNaOH (cold, 180mL) handle this material.With ethyl acetate (3 * 200mL) aqueous phase extracted.With 2N NaOH (cold, 75mL) wash this organic phase, wash this organic phase then with water, be neutral (pH value 7) up to washes.Dry (sodium sulfate) this organic phase also concentrates.Produce: 6.7g is the S-Venlafaxine (1) of white crystalline solid.m.p.104.5℃-106℃。[α]
D 23＝+13.9(c＝1.6，MeOH)。Chirality HPLC:98% enantiomeric excess.
1H-NMR (CDCl
3): referring to above
S-Venlafaxine N-oxide compound (3)
According to 4 programs of describing, by FAI (106796) obtained crude material (2.2g, 7.5mmol).Obtain pure 3 by column chromatography (gradient methylene dichloride: methyl alcohol, 9: 1 → methylene dichloride: the ammonia of 3.5M in methyl alcohol, 9: 1).Produce: 1.70g (5.8mmol, 78%) is 3 of little yellow solid.[α]
D 23＝-20.8(c＝1.0，MeOH)。
1H-NMR(300MHz，CDCl
3)：δ7.09(d，2H，J＝8.5Hz)，6.84(d，2H，J＝8.5Hz)，4.16(m，1H)，3.79(s，3H)，3.51(dd，1H，
2J＝3.8Hz，
3J＝12.7Hz)，3.41(m，1H)，3.27(s，3H)，3.07(s，3H)，1.78-1.60(m，3H)，1.60-1.35(m，4H)，1.29-1.01(m，2H)，0.95-0.76(m，1H)。
R-Venlafaxine N-oxide compound (4)
(2,1.0g 3.4mmol) is dissolved in methylene dichloride (60mL) with the R-Venlafaxine.This solution is cooled to-10 ℃.Interpolation m-CPBA (fresh, 2.9g, 7.3mmol).Stirred this suspension 30 minutes down at-10 ℃.TLC detects to disclose fully and transforms.Add K
2CO
3(5.0g 36mmol), and stirred this mixture 30 minutes under 0 ℃.Add methylene dichloride (50mL) and filtering suspension liquid.Dry this filtrate also concentrates.As indicated above, this raw product of purifying.Produce: 0.9g (3.0mmol, 90%) white solid.[α]
D 23: do not measure.
1H-NMR (300MHz, CDCl
3): referring to above.
O-demethyl-S-Venlafaxine (5)
At N
2Down, (18mL, 0.1mol) solution in anhydrous tetrahydro furan (120mL) is cooled to-10 ℃ with diphenyl phosphine.(2.5M is in hexane, 50mL) with additional tetrahydrofuran (THF) (40mL) to add n-BuLi.Stirred this mixture 30 minutes down at-10 ℃, allowable temperature is raised to 0 ℃ then.Under this temperature, and interpolation S-Venlafaxine (1,6.2g, 23mmol) solution in tetrahydrofuran (THF) (60mL).Stirred this mixture 2 hours, allowable temperature is raised to room temperature simultaneously, keeps 16 hours under reflux temperature subsequently.
With this reaction mixture cool to room temperature, pour into 2N HCl (cold, 300mL) in and stirred 10 minutes.Washing (ethyl acetate, 3 * 300mL) waters, then by means of slow (! ) interpolation NaHCO
3Neutralize (pH value 7), and extraction (ethyl acetate, 6 * 300mL).Dry (Na
2SO
4) this organic phase and concentrated in a vacuum.Be suspended in residue in the ethyl acetate (100mL) and stirred 30 minutes.On glass filter, collect solid, and with the ethyl acetate washing, up to the smell that no longer can detect diphenyl phosphine.White solid.Output: 4.6g (17.5mmol, 76%).m.p.237.3℃-237.9℃。[α]
D 23＝+17.0(c＝0.88，MeOH)。
1H-NMR(300MHz，DMSO-d
6)：δ9.12(br，1H)，6.94(d，2H，J＝8.3Hz)，6.62(d，2H，J＝8.3Hz)，5.37(br，1H)，2.98(m，1H)，2.71(t，1H，J＝5.8Hz)，2.34(m，1H)，2.14(s，6H)，1.64-1.22(m，7H)，1.20-0.78(m，3H)。
O-demethyl-R-Venlafaxine (6)
As above, (5.0g, 18mmol) beginning is used at hexane (2.5M, 41mL) diphenyl phosphine in (14mL) and n-BuLi from the R-Venlafaxine.Output: 3.8g (14.5mmol, 80%).m.p.235.5℃-237.1℃。[α]
D 23＝-21.3(c＝0.9，MeOH)。
1H-NMR (300MHz, DMSO-d
6): referring to above.
O-demethyl-S-Venlafaxine N-oxide compound (7)
(5,1.5g 5.7mmol) is suspended in the methylene dichloride (100mL) with O-demethyl-S-Venlafaxine.This suspension is cooled to-10 ℃.Interpolation m-CPBA (4.8g, 12mmol).Stirred this suspension 60 minutes down at-10 ℃.TLC detects to disclose fully and transforms.Add K
2CO
3(7.5g 54mmol), and stirred this mixture 30 minutes under 0 ℃.Add methylene dichloride (100mL) and filtering suspension liquid.In methyl alcohol (300mL), stir residue, and filter once more.Concentrate the filtrate (output: 7.1g) that merges in a vacuum.
By this material of column chromatography purifying: raw product is dissolved in methyl alcohol (20mL), is added on this post (silicon-dioxide in the methylene dichloride), use the NH of methylene dichloride: 7M in methyl alcohol subsequently with methylene dichloride (200mL)
3, 9: 1 wash-outs.Produce: be 1.15g (4.1mmol, the 72%) compound 7 of little yellow solid.[α]
D 23＝-26.8(c＝0.8，MeOH)。
1H-NMR(300MHz，DMSO-d
6)：δ9.66(br，1H)，6.98(d，2H，J＝8.3Hz)，6.69(d，2H，J＝8.3Hz)，3.88(m，1H)，3.55(dd，
2J＝2.4Hz，
3J＝12.7Hz，1H)，3.34(br，1H)，3.20(dd，
2J＝2.4Hz，
3J＝12.7Hz，1H)，3.14(s，3H)，2.95(s，3H)，1.69-1.20(m，6H)，1.11-0.66(m，4H)。
O-demethyl-R-Venlafaxine N-oxide compound (8)
As above, (6,1.5g 5.7mmol) begins from O-demethyl-R-Venlafaxine.Produce: the little yellow solid of 1.20g (4.3mmol, 75%).[α]
D 23＝+16.3(c＝0.8，MeOH)。
1H-NMR (300MHz, DMSO-d
6): referring to above.
Embodiment 3: pharmacological method
By CEREP (128, rue Danton, 92500 Rueil-Malmaison, French) or at Solvay Pharmaceuticals B.V. (C.J.van Houtenlaan 36,1381 CPWeesp, Holland) use the program of extensively putting down in writing to obtain the external affinity at neurotransmitter re-uptake position.What measure is affinity to serotonin (Tatsumi, 1999), norepinephrine (Pacholczyk, 1991) and dopamine reuptake position (Pristupa, 1994).
[
3H]-the external function of serotonin reuptake transporter suppresses: with male rat (WistarHsd/Cpb:WU; 175-200g) sacrificed by decapitation is promptly removed hemicerebrum, and preparation P2-synaptosome part.Not existing or exist under the test compound, under 37 ℃, the preincubation synaptosome is 15 minutes in the substratum that contains MAO inhibitor Pargyline (7 μ M).Subsequently, this synaptosome is exposed to [
3H]-serotonin (0.2mM ultimate density) 10 minutes.Stop by filtering with collector [
3H]-serotonin picked-up and remove unconjugated radioactive substance by thorough washing.Make filter plate dehydration with synaptosome, and by the Betaplate liquid scintillation counting(LSC) measure exist [
3H]-amount of serotonin.Will to [
3H]-the inhibition effect of the picked-up of serotonin is expressed as pIC
50Value, it is the negative logarithm that reaches the concentration of the half that the maximum of radiolabeled neurotransmitter picked-up suppresses.The pIC that provides
50Value is 2-9 the mean value of testing that a-type double carries out.With test compound (10
-2M is dissolved in DMSO) be diluted in the Krebs Ringer damping fluid and reach 10
-8To 10
-5The experimental concentration of M.Further experimental detail is described in (Coyle, 1969).
[
3H]-the external function of norepinephrine reuptake suppresses: with male rat (WistarHsd/Cpb:WU; 175-200g) sacrificed by decapitation is promptly removed hypothalamus, and prepares rough synaptosome part.Not existing or exist under the test compound, under 37 ℃, the preincubation synaptosome is 10 minutes in the substratum that contains MAO inhibitor Pargyline (7 μ M).Subsequently, this synaptosome is exposed to [
3H]-norepinephrine (0.4mM ultimate density) 15 minutes.Stop by filtering with collector [
3H]-norepinephrine uptake and remove unconjugated radioactive substance by the thorough washing program.Drying has the filter plate of synaptosome, and by the Betaplate liquid scintillation counting(LSC) measure to exist [
3H]-amount of norepinephrine.Will to [
3H]-the inhibition effect of the picked-up of norepinephrine is expressed as pIC
50Value, it is the negative logarithm that reaches the concentration of the half that the maximum of radiolabeled neurotransmitter picked-up suppresses.The pIC that provides
50Value is 2-9 the mean value of testing that a-type double carries out.With test compound (10
-2M is dissolved in DMSO) be diluted in the Krebs Ringer cushion and reach 10
-8To 10
-5The experimental concentration of M.Further experimental detail is described in (Coyle, 1969).
[
3H]-the external function of dopamine reuptake suppresses: with male rat (WistarHsd/Cpb:WU; 175-200g) sacrificed by decapitation; Promptly remove striatum; And prepare rough synaptosome part (P2) by homogenizing and centrifugation.Not existing or exist under the test compound, under 37 ℃, containing oxidase inhibitor Pargyline (7 * 10
-6M) preincubation synaptosome 15 minutes (Coyle, 1969) in the substratum.Add subsequently, [
3H]-Dopamine HCL (2 * 10
-7The M ultimate density) and continued incubation 10 minutes.Stop by filtering [
3H]-dopamine uptake and with phosphate buffered saline (PBS) washing synaptosome four times.By the Betaplate liquid scintillation counting(LSC) measure in the synaptosome [
3H] amount of Dopamine HCL.10
-9M to 10
-5Test compounds in the concentration range of M.Use pIC
50Value (medicine causes the negative logarithm of the concentration when 50% picked-up suppresses) expression to [
3H]-the inhibition effect of the picked-up of Dopamine HCL.A-type double carries out the inhibition of DA picked-up.
People's colon models TIM2 (TNO intestines model 2) is the dynamicmodel of people's large intestine of condition in the analogue body.It is the artificial Digestive tract that is confirmed by many researchs (Minekus, 1999).
Venlafaxine-N-oxide compound is the prodrug of parent compound.They can be used for treating the disease that available Venlafaxine is effectively treated (even side effect is arranged): the dysthymia disorders, generalized-anxiety disorder, obsessional idea that comprises major depressive disorder and behavior disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and with menopause relevant vasomotor symptoms, also be called ' hot flush '.
Embodiment 4: pharmacokinetics and pharmacology test result
Venlafaxine and its N-oxide compound of being formulated in respectively in 40%HP β CD or 1% methylcellulose are used (intravenously (i.v.) or oral (p.o.)) respectively to male NMRI mouse (3 animals of each time point), after this analyze their blood plasma and two kinds of compounds in the brain by LC-MS (referring to method above).The mean value of data calculated (n=3), and be collected in the table 1.
In mouse, Venlafaxine only minimum level ground metabolism becomes its N-oxide compound: its concentration in blood plasma is from being no more than the 1-2% of parent compound, and in brain, only can find trace.When using Venlafaxine-N-oxide compound itself, it is reduced into parent compound.After the i.v. of Venlafaxine-N-oxide compound uses about one hour, the Venlafaxine concentration in blood plasma and the brain surpassed the concentration of N-oxide compound.Effect is more remarkable after oral: the concentration of Venlafaxine rises to the high 10-100 of the concentration level doubly than N-oxide compound in blood plasma and brain.
Add in the TIM2 model described chamber (120ml) of (referring to above, Minekus, 1999) being suspended in Venlafaxine in 1% methylcellulose-N-oxide compound (1mg).Obtain sample in the different timed intervals from described chamber and dialyzate (latter is the model that is used for the vescular bed of intestines), and analyze Venlafaxine-N-oxide compound and Venlafaxine: table 2:
From top result as can be seen, in 2 hours, Venlafaxine N-oxide compound almost quantitatively has been reduced into Venlafaxine after administration.Because many TIM2 of studies confirm that are the external model that the gastrointestinal conditions among the living person is had high predictive value, so can expect, in the people, after oral, Venlafaxine N-oxide compound also will be reduced into Venlafaxine: it will be a prodrug.
*For the i.v. administration, with C
MaxValue is extrapolated to T
0(time zero)
The data that provide from above as can be seen, the clearance rate of Venlafaxine, the volume of distribution and bioavailability are than those high twices of its pyridine N-oxides.Significantly, these two kinds of compounds have different pharmacokinetics performances.The data that provide from table 1 it can also be seen that Venlafaxine-N-oxide compound penetrates brain hardly: therefore, and remarkable different brain/blood plasma ratio.
The external pharmacology data of listing in the last table clearly illustrates that Venlafaxine is the strongest as the inhibitor effect of serotonin reuptake transporter.Its (R)-and (S)-enantiomer only shows MIN difference.Find major metabolite O-ODV and Venlafaxine equivalence,, and be its independent enantiomeric forms all as racemic modification.
The N-oxide compound (as racemic modification and independent (R)-or (S)-enantiomer) of finding Venlafaxine and O-demethyl-Venlafaxine is non-activity in fact.
Embodiment 5: pharmaceutical preparation
For clinical application, the N-oxide compound of general formula (1) is formulated in the pharmaceutical composition, this pharmaceutical composition is an important and novel embodiment of the present invention, because they comprise compound disclosed herein, more particularly, specific compound.The type of operable pharmaceutical composition comprises: tablet, chewable tablet, capsule (comprising micro-capsule), solution, parenteral solution, ointment (emulsifiable paste and gel), suppository, suspension and disclosed herein, or for a person skilled in the art according to this specification sheets and common practise and conspicuous other type.For example, activeconstituents can also be in cyclodextrin, their ether or the clathrate complex form in their ester.That described composition is applicable to is oral, in the intravenously, subcutaneous, tracheae, segmental bronchus, nose, lung, transdermal, buccal mucosa, rectum, parenteral or other administration.Pharmaceutical preparation comprises the N-oxide compound of the general formula (1) of acceptable assistant, thinner and/or carrier fusion at least a and at least a pharmacy.The total amount of activeconstituents is suitably about 0.1% (w/w)-about 95% (w/w) of preparation, is suitably 0.5%-50% (w/w), preferred 1%-25% (w/w).In some embodiments, the amount of activeconstituents is greater than about 95% (w/w) or less than about 0.1% (w/w).
Pass through usual method, use for example liquid or solid of auxiliary substance, the powdery composition is liquid or solid weighting agent commonly used and expand agent, solvent, emulsifying agent, lubricant, correctives, tinting material and/or buffer material in the pharmacy for example, compound of the present invention can be made the formulation that is suitable for administration.Normally used auxiliary substance comprises magnesiumcarbonate, titanium dioxide, lactose, sucrose, Sorbitol Powder, mannitol and other sugar or sugar alcohol, talcum, milk-protein, gelatin, starch, amylopectin, Mierocrystalline cellulose and derivative thereof, animal oil and vegetables oil for example Oils,glyceridic,cod-liver, Trisun Oil R 80, peanut oil or sesame oil, polyoxyethylene glycol and solvent (for example sterilized water) and monohydroxy-alcohol or polyvalent alcohol (for example glycerine), and disintegrating agent and lubricant for example Magnesium Stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax.Mixture can be processed into particle then or be pressed into tablet.Use following composition to prepare tablet:
Said components fusion and compacting are formed the tablet of every heavy 230mg.
Before mixing the formation preparation, can be individually with activeconstituents and other non-active ingredient pre-mixing.Mix the formation preparation with non-active ingredient before, can also be with the activeconstituents intermingling.
Soft gelatin capsule can adopt and contain the capsule preparation of mixture that activeconstituents of the present invention, vegetables oil, fat or other are suitable for the carrier of soft gelatin capsule.Hard gelatin capsule can comprise the particle of activeconstituents.Hard gelatin capsule can also comprise activeconstituents and solid, powdery composition, for example lactose, sucrose, Sorbitol Powder, mannitol, yam starch, W-Gum, amylopectin, derivatived cellulose or gelatin.
The dosage device that is used for rectal administration can be prepared as (i) suppository form, and this suppository comprises and neutral fat matrix blended active substance; (ii) gelatin rectal capsule form, this capsule comprise with vegetables oil, paraffin oil or are suitable for other carrier blended active substance of gelatin rectal capsule; The little enema forms that (iii) prepares; Or (iv) do slight irrigation Enteral formulations form, said preparation just reconstituted in the solvent that is fit to before being about to administration.
Liquid preparation can be prepared into syrup, elixir, spissated drops or suspension, the solution or the form of suspension that for example contain activeconstituents and rest part, this rest part for example are made of the mixture of sugar or sugar alcohol and ethanol, water, glycerine, propylene glycol and polyoxyethylene glycol.If necessary, this type of liquid preparation can comprise tinting material, correctives, sanitas, asccharin and carboxymethyl cellulose or other thickening material.Liquid preparation can also be prepared into dry powder form, and it used the solvent reconstruct that is fit to before using.The solution that is used for administered parenterally can be prepared as the solution of preparation of the present invention acceptable solvent in pharmacy.These solution can also comprise stable composition, sanitas and/or buffer composition.The solution that is used for administered parenterally can also be prepared as dry preparation, and it used the solvent reconstruct that is fit to before using.
According to the present invention, preparation and ' kit box ' also are provided, it comprises one or more containers that one or more compositions of pharmaceutical composition of the present invention are housed, and is used for therapeutic treatment.Such container can be with various written materials, working instructions for example, or the letter of information of the form of the statutory regulation of production, use or the sale of management medicament production, this letter of information has reflected the approval of described department for production, application or the sale of people or animal doctor's administration.The purposes of preparation of the present invention in making medicament, this medicament is used for the treatment of depression, comprise major depressive disorder, generalized-anxiety disorder, obsessional idea and behavior disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and the vasomotor symptoms relevant with menopause, also be called ' hot flush ', with the therapeutic treatment method or comprise with the treatment effective total amount at least a general formula (1) the N-oxide compound with itself or, under the situation of prodrug, after being administered to the patient who suffers from following disease: the dysthymia disorders that comprises major depressive disorder, generalized-anxiety disorder, obsessional idea and behavior disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and the vasomotor symptoms relevant with menopause also are called ' hot flush '.
For instance and without limits, provided the multiple medications composition, it comprises and is used for that whole body is used or the preferred active compound of topical application.Other compound of the present invention or its combination can be used for replacing described compound (or with described compound addition).The concentration of activeconstituents can change in the wide region of this paper discussion.The amount of the composition that can comprise and type are to know in this area.
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Claims (19)
1. the N-oxide compound and tautomer, steric isomer, hydrate and the solvate that have general formula (1):
Wherein asterisk (
*) the mark unsymmetrical carbon, R
1Be H or CH
3
2. according to the N-oxide compound of claim 1, it is substantially free of 1-[2-(dimethylamino)-1-(4-methoxyl group-phenyl) ethyl]-hexalin and 1-[2-(dimethylamino)-1-(4-hydroxyl-phenyl) ethyl]-hexalin and tautomer, steric isomer, salt, hydrate and solvate.
3. according to N-oxide compound and tautomer, steric isomer, hydrate and solvate, the wherein R of claim 1
1Be CH
3
4. according to the N-oxide compound of claim 3, it is substantially free of 1-[2-(dimethylamino)-1-(4-methoxyl group-phenyl) ethyl]-hexalin and tautomer, steric isomer, salt, hydrate and solvate.
5. according to N-oxide compound and tautomer, steric isomer, hydrate and solvate, the wherein R of claim 1
1Be H.
6. according to the N-oxide compound of claim 5, it is substantially free of 1-[2-(dimethylamino)-1-(4-hydroxyl-phenyl) ethyl]-hexalin and tautomer, steric isomer, salt, hydrate and solvate.
7. according to each N-oxide compound among the claim 1-6, or the acceptable salt of any aforesaid pharmacology, hydrate or solvate, described compound is the optically active enantiomer.
8. according to N-oxide compound or the acceptable salt of any aforesaid pharmacology, hydrate or the solvate of claim 7, it is (R)-enantiomer.
9. according to N-oxide compound or the acceptable salt of any aforesaid pharmacology, hydrate or the solvate of claim 7, it is (S)-enantiomer.
10. N-oxide compound according to Claim 8, it is substantially free of (S)-1-[2-(dimethylamino)-1-(4-methoxyl group-phenyl) ethyl]-hexalin and (S)-1-[2-(dimethylamino)-1-(4-hydroxyl-phenyl)-ethyl]-hexalin and the acceptable salt of pharmacology, hydrate and solvate.
11. according to the N-oxide compound of claim 9, it is substantially free of (R)-1-[2-(dimethylamino)-1-(4-methoxyl group-phenyl) ethyl]-hexalin and (R)-1-[2-(dimethylamino)-1-(4-hydroxyl-phenyl)-ethyl]-hexalin and the acceptable salt of pharmacology, hydrate and solvate.
12. a medicament, it comprises according to each compound among the claim 1-11, or its hydrate or solvate.
13. pharmaceutical composition, it is on comprising pharmacy in acceptable carrier and/or at least a pharmacy the acceptable auxiliary substance, the compound that also comprises among at least a claim 1-11 of pharmacological activity amount each, or its hydrate or solvate are as activeconstituents.
14. combined pharmaceutical formulation, it comprises the N-oxide compound of (i) general formula (1), or its hydrate or solvate, (ii) another kind of therapeutical agent, be used for simultaneously, separately or order be used for the treatment of the dysthymia disorders, generalized-anxiety disorder, obsessional idea and the behavior disorder that comprise major depressive disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and ' hot flush '.
15. according to the combined pharmaceutical formulation of claim 14, wherein said other therapeutical agent is Venlafaxine or O-ODV.
16., be used for the treatment of the dysthymia disorders, generalized-anxiety disorder, obsessional idea and the behavior disorder that comprise major depressive disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and ' hot flush ' according to each compound among the claim 1-11.
17. be used for the purposes of pharmaceutical compositions according to each compound among the claim 1-11, this pharmaceutical composition is used for the treatment of the dysthymia disorders, generalized-anxiety disorder, obsessional idea and the behavior disorder that comprise major depressive disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and ' hot flush '.
18. be used for the purposes of pharmaceutical compositions according to the combination preparation of claim 15, this pharmaceutical composition is used for the treatment of the dysthymia disorders, generalized-anxiety disorder, obsessional idea and the behavior disorder that comprise major depressive disorder, social anxiety disorder, Phobias, general dysthymia disorders, diabetic neuropathy, migraine and ' hot flush '.
19. preparation, is characterised in that the compound of using oxygenant oxidation general formula (a) is to produce the compound of general formula (1) according to the method for the compound of claim 1
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| EP07111028.2 | 2007-06-26 | ||
| PCT/EP2008/057939 WO2009000797A1 (en) | 2007-06-26 | 2008-06-23 | N-oxides of venlafaxine and o-desmethylvenlafaxine as prodrugs |
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| CN103570669A (en) * | 2013-10-31 | 2014-02-12 | 吉林大学 | Brain-targeted O-desmethylvenlafaxine phenolic ester prodrug and preparation method and applications thereof |
| CN111072505A (en) * | 2019-12-27 | 2020-04-28 | 合肥华方医药科技有限公司 | Preparation method of venlafaxine impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI490189B (en) * | 2011-05-16 | 2015-07-01 | 江蘇豪森醫藥集團有限公司 | O-demethylation of venlafaxine hydrochloride hydrate and their preparation method |
-
2008
- 2008-06-23 JP JP2010513873A patent/JP2010531326A/en not_active Withdrawn
- 2008-06-23 BR BRPI0813658A patent/BRPI0813658A2/en not_active IP Right Cessation
- 2008-06-23 TW TW097123310A patent/TW200916092A/en unknown
- 2008-06-23 AR ARP080102685A patent/AR068978A1/en not_active Application Discontinuation
- 2008-06-23 CN CN2008800220292A patent/CN101939293A/en active Pending
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2009
- 2009-12-04 ZA ZA200908631A patent/ZA200908631B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570669A (en) * | 2013-10-31 | 2014-02-12 | 吉林大学 | Brain-targeted O-desmethylvenlafaxine phenolic ester prodrug and preparation method and applications thereof |
| CN111072505A (en) * | 2019-12-27 | 2020-04-28 | 合肥华方医药科技有限公司 | Preparation method of venlafaxine impurity |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010531326A (en) | 2010-09-24 |
| AR068978A1 (en) | 2009-12-23 |
| ZA200908631B (en) | 2010-08-25 |
| BRPI0813658A2 (en) | 2016-10-18 |
| TW200916092A (en) | 2009-04-16 |
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