CN1933817A - Disintegrating tablets comprising licarbazepine - Google Patents

Abstract

The invention relates to pharmaceutical compositions comprising 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (also referred to as ''licarbazepine'') as drug substance.

Description

The disintegrating tablet that comprises licarbazepine

The present invention relates to comprise 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide (being also referred to as " licarbazepine (licarbazepine) " in this manual) is as the pharmaceutical composition of medicine.

The term licarbazepine that uses in this description refers to (S)-10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide and (R)-10, the racemic mixture of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide.

In the present invention, licarbazepine, comprise (S)-10 of one of two kinds of excessive enantiomer, 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide and (R)-10, one of the mixture of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide or pure substantially or pure enantiomers of licarbazepine all can be used as medicinal application and are called as " chemical compound of the present invention " hereinafter together.

Licarbazepine (being also referred to as MHD) be known in the document [referring to, for example, people such as Schuetz H.., Xenobiotica (GB), 16 (8), 769-778 (1986)] and can synthesize preparation, for example from oxcarbazepine (oxcarbazepine), according to the method such as the US-3 of routine, the method preparation of describing in 637,661.

Pure enantiomers of licarbazepine can begin to obtain by known procedures from racemic modification.For example, can be by forming diastereomer, perhaps according to the description among the WO-02/092572 for example, form salt by chiral acid with enantiomer-pure, perhaps by means of chromatograph,, use the chromatograph substrate that contains chiral ligand and racemic modification is separated into its enantiomer for example by HPLC.In one embodiment of the invention, pure enantiomers of licarbazepine is to prepare by the enantioselectivity method of describing among the embodiment.

Licarbazepine is pointed out to be suitable for to treat physical psychological, epilepsy, trigeminal neuralgia and cerebral spasticity.Proved that licarbazepine racemic modification and its pure enantiomer are equivalent for epilepsy.The mechanism that chemical compound of the present invention is brought into play its anticonvulsant action also is not fully clear and definite, but their activity may partly be because the effect of ion flow leap neuronal cell film causes.But the pharmacokinetics of The compounds of this invention, absorption site and mechanism of action are not also at length understood.

Licarbazepine is slightly soluble in water (3.2mg/mL, 25 ℃).Given this physical property, the parenteral formulation of licarbazepine can be according to the method preparation as describing among the EP-1 033 988.Although known non-parenteral dosage forms has multiple advantage, also need to set up the more excellent peroral dosage form of The compounds of this invention.The fluctuation of The compounds of this invention haemoconcentration when one of problem that the application peroral dosage form may occur is repeat administration, this fluctuation may be with side effect.

After deep test, unexpectedly found to be administered once every day and the good especially toleration and the good more excellent oral controlled release medicine composition of bioavailability have been arranged in various patient groups.

Therefore, on the one hand, the present invention relates to the oral controlled release medicine composition (being called as " peroral dosage form of the present invention " hereinafter) that be administered once and comprise at least a The compounds of this invention suitable every day, said composition is especially showed the low index of oscillation for better toleration and is had suitable C _MinThe consecutive symptom control of (minimum plasma concentration) value, and have high AUC (area under curve) and low C _MaxThe advantage of (maximum plasma concentration) value.

Peroral dosage form of the present invention may show sizable advantage than other peroral dosage form, and it shows that they use more conveniently and/or safer for the patient, and increased the compliance of patient to treatment.The patient only needs to take every day once peroral dosage form of the present invention.

The term that uses in this description " once a day " is meant every 20-28 hour once, and particularly per 24 hours once.

Preferred peroral dosage form of the present invention has the form of disintegrating tablet, and this disintegrating tablet contains the controlled release granule that comprises chemical compound of the present invention, particularly licarbazepine.In this peroral dosage form, chemical compound of the present invention, licarbazepine particularly, can be in controlled release granule with the content of the 60-90% that accounts for controlled release granule weight, be preferably 75-85%, as be approximately 80% content or account for the content of the 50-80% of total composition weight, be preferably 60-70%, as be approximately 65% content and exist.

Chemical compound of the present invention, particularly licarbazepine are preferably used promptly particulate median particle size (x with the form of coarse particles ₅₀) be about 150-300 μ m, be preferably about 200-250 μ m, more preferably about 210-230 μ m is as about 220 μ m.

In one embodiment of the invention, peroral dosage form comprises at least a retarding agent in controlled release granule, this retarding agent is selected from polymethacrylates, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose, is preferably polymethacrylates and ethyl cellulose.

Can use the polymethacrylates that is generally used for tablet, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose, and with as a reference about the lot of documents of the polymethacrylates that is fit to and cellulose derivative, " the Lexikon derHilfsstoffe " of Fiedler particularly, the 4th edition, ECV Aulendorf (1996), be called as " LdH " hereinafter, and " Handbook of Pharmaceutical Excipients ", Wade and Weller, the third edition (2000), be called as " HoPE " hereinafter, these documents are incorporated in this description as a reference.

Preferred retarding agent is relative molecular weight 〉=100 for example in the peroral dosage form of the present invention, the polymethacrylates of 000Da, the copolymer that for example is called as the acrylic or methacrylic acid esters of Eudragit, Eudragit RL 30D (HoPE for example, 402 pages), and ethyl cellulose, for example available from the Aquacoat of FMC ^The Aquacoat of-30% weight, or available from the Surelease of Colorcon ^

Polymethacrylates can be in controlled release granule with the content of the 5-25% that accounts for controlled release granule weight, be preferably 10-20%, the content as about 15% exists.

Ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose can be in controlled release granule with the content of the 2-10% that accounts for controlled release granule weight, be preferably 4-8%, the content as about 6% exists.

On the other hand, the present invention relates to comprise the oral controlled release medicine composition of licarbazepine, it is characterized in that, in use, 70-90%, the described licarbazepine of preferred 80-90% discharged in 6 hours, and for the dosage form of 500mg, this confirms by dissolution test outside the standard body in the time of 37 ℃, in the phosphate buffer of pH about 6.8.

Clinical research for example, can realize by conventional method.For example, can realize by the The compounds of this invention of in 7 days or more days, using 500mg dosage.Usually comprise at least 6 examples, for example 10 routine experimenters.In this research, can determine release characteristics, bioavailability, food effect, safety, toleration, the C of peroral dosage form of the present invention _MaxAnd/or AUC.

Bioavailability of medicament depends on its physicochemical properties, and for example dissolubility, and pharmacokinetic property is as position, speed and the degree that absorbs.In addition, known food can cause the physiological change in gastrointestinal (GI) road.These change except causing the delayed gastric emptying, can also stimulate bile flow and change pH.Food can also change the chamber metabolism and with the interaction of the physics of medicine or chemistry.Therefore, no wonder food can also influence bioavailability of medicament.The term that uses in this description " food effect " is meant that the bioavailability of medicine in the experimenter of state after the meal is different from the bioavailability among the experimenter of medicine at fasting state.Food effect be complicated and be difficult to expect and will depend on for example character of diet, as its nutrient content, liquid volume, energy content and temperature.Therefore, for certain drug, only having or not of food effect could be determined after detailed test.

If bioavailability of medicament can because the patient be after the meal or fasting state and different, this is undesirable so.This is inconvenient at least for the patient, because they have to arrange the relative time of having a dinner and taking medicine.

Therefore, the peroral dosage form of surprisingly having found licarbazepine can deliver medicine to the patient and need not consider patient's condition, and promptly the patient is after the meal or fasting state.

Therefore, the present invention relates to peroral dosage form of the present invention on the other hand, and this dosage form does not have food effect when delivering medicine to the patient.

On the other hand, this aspect relates to packing, and this packing comprises the written document of peroral dosage form of the present invention and for example operation instruction, and described description is stipulated after the meal or the patient under the fasted conditions can take this peroral dosage form equally.

More particularly, the present invention relates to peroral dosage form of the present invention and for example packaged in combination of written description, described description stipulate this peroral dosage form can with or not with food with clothes.

Having or not of food effect can be according to method well known in the art by using AUC measurement result and/or C _MaxMeasurement result is come quantitatively.Typically, this measurement result is regularly to take biological fluid and with the serum-concentration of medicine such as licarbazepine the time mapping is drawn.The value of gained is represented many values of the experimenter who comes from patient group and is therefore represented all patient groups' meansigma methods.By comparing average A UC and/or C _MaxValue can determine whether medicine such as licarbazepine demonstrate food effect.

" after the meal " experimenter can be considered to be receiving at least 10 hours experimenter of fasting before the high fat diet of FDA approval of standard simply.Then, medicine such as licarbazepine can for example be obeyed together with water in 5 minutes thereafter after just finishing diet.Preferably certain hour should not eat food again in 4 hours behind administration such as licarbazepine, but can allow to drink a spot of water after administration such as licarbazepine were as 2 hours.

" fasting " experimenter can take medicine such as licarbazepine with water after at least 10 hours fasting.Afterwards, food should be do not eaten again in as 4 hours, but after administration such as licarbazepine were as 2 hours, a spot of water can be drunk at certain hour.

This description described " high fat diet of the FDA of standard approval " can comprise that expection can provide any diet of the fluctuation of the maximum that the existence owing to food in the gastrointestinal tract causes.Described high fat diet typically can comprise its caloric value of 50% in fat.Representational example can be 2 butter fried egg, 2 bacon, 2 butter Toasts, 4 ounces of chips and 8 ounces of milk.

In order to study the influence of food to drug bioavailability, can use any conventional study design as known in the art, for example at random, equilibrated single dose, two kinds of Therapeutic Method, two kinds of cycles, two kinds of orders, orthogonal design.Analysis can be used the institute from SAS, Cary, and the software of North Carolina carries out as SAS PROC GLM.

Be used for determining the bioavailability of peroral dosage form of the present invention, the suitable research design that comprises food effect be at random, open labelling, single port clothes dosage, quadrature research, wherein can the bioavailability of peroral dosage form of the present invention of The compounds of this invention and the solution of same The compounds of this invention will be comprised, the bioavailability that randomly also comprises the oxcarbazepine thin membrane coated tablet compares, and is estimating food effect after the meal or in the healthy male subjects of fasting state.

Medicine therein is in the research of for example licarbazepine, and oxcarbazepine thin membrane coated tablet (600mg) and the peroral dosage form of the present invention that comprises as the 500mg licarbazepine can deliver medicine to the experimenter simultaneously with the 240mL tap water.The clinical administration form (500mg) of the licarbazepine of sending with powder type needs to be dissolved in the tap water before administration.In needing the treatment cycle of fasted conditions, research medicine administration after at least 10 hours overnight fast of single dose.In needing the treatment cycle of fed conditions, require higher fatty acid breakfast of the FDA approval of each experimenter food sanitation standard in preceding 30 minutes of administration.In needing the treatment cycle of fasted conditions, do not have breakfast before the administration, and the experimenter needs continuous fasting up to taking medicine back 4 hours.Safety and toleration monitoring comprise the continuous monitoring of adverse events, physical examination, blood pressure and pulse rate measurements, ECG record and routine laboratory test (hematochemistry, urinalysis and hematology).

In first cycle of 7 days, the experimenter will take one of peroral dosage form of the present invention under fasted conditions, and the experimenter will carry out same treatment under condition after the meal in second period.Before administration first time The compounds of this invention, the experimenter night with minimum 10 hours (cycle 1) of overnight fast.Next take medicine in for example breakfast time, after the reasonable time interval is as administration, extracted the pharmacokinetics blood sample in 0.5,1,2,3,4,6,8,10,12,14,16,18,20,22,24,32 and 48 hour and be used for analysis.

The absorption feature of The compounds of this invention can be quantitative by the AUC measurement result of single dose or stable state.

The constant plasma levels of The compounds of this invention shows that the plasma concentration of The compounds of this invention shows as the low index of oscillation.The C of The compounds of this invention _MinAnd C _MaxValue can remain on one among a small circle in.In order to measure C _MinAnd C _MaxBetween fluctuation, measure the plasma concentration of The compounds of this invention in stable state, and the index of oscillation is according to (C _Max-C _Min)/C _Av(C wherein _MaxBe maximum concentration, C _MinBe least concentration, C _AvBe mean concentration, the certain hour when stable state is observed at interval as in 24 hours) calculate.

C _MinAnd C _MaxLow fluctuation can avoid the peak value of The compounds of this invention plasma concentration, this peak value is virose for the patient.Low fluctuation can provide better toleration and safety for the patient with the The compounds of this invention treatment.

Therefore, on the other hand, the present invention relates in the patient of oral licarbazepine therapy, reduce the multifarious method of licarbazepine bioavailability level in the individuality, described method comprises that administration comprises the of the present invention peroral dosage form of licarbazepine as medicine, this dosage form is at random delivering medicine to after the meal or the patient of fasting state, does not for example all have food effect during administration at any time.

On the other hand, the present invention relates to licarbazepine and be used for the treatment of purposes in the medicine of patients with affective disorders in preparation.

The term that uses in this description " affective disorder " comprises, but be not limited to, single and two-phase depression, bipolar disorder, premenstruum dysthymic disorder, postpartum depression, menopause retarded depression, depression that neural degeneration is relevant, occur in that mental stimulant is taken in depression after stopping, needed the stable psychotic state of behavior such as epilepsy, schizophrenia and too emotion change.

Peroral dosage form of the present invention can be observed in the clinical research of the animal experiment of standard or standard in the effectiveness of treatment in the affective disorder, is in bipolar disorder patient's the clinical research of about 500-3000mg every day at the dosage range of administration such as licarbazepine for example.

Peroral dosage form of the present invention can prepare with conventional method by blending ingredients.The mixture that generates can be a powder type, and this powder can be with conventional tablet machine compacting in flakes.

Simply, peroral dosage form of the present invention can be used conventional tabletting method by The compounds of this invention and for example conventional tabletting excipient are suppressed to form label and next the label coating to be prepared.Label can be used conventional method of granulating, and for example wet method or dry granulation and ensuing tabletting and coating prepare.Method of granulating is recorded in for example R.Voigt, and " Lehrbuch derPharmazeutischen Technologie ", Verlag Chemie, sixth version is in the 156-169 page or leaf.

Granule can for example be used and become known for producing " making up (built-up) " granule and " broken (broken-down) " particulate wet granulation method preparation by known method preparation itself.

Making up particulate formation method can comprise; for example; in for example rotary drum granulator, pan pelletizer, disc type granulator or fluid bed; by spraying-drying or spraying-curing; in the granulation mass spraying, carrying out drying with granulation solution, or for example operating discontinuously in fluid bed, batch mixer or the drum-type spray dryer.

Depend on the method that is adopted, granulation mass can be the form of premix or for example can pass through The compounds of this invention and one or more mixed with excipients are obtained.Wet granular is preferably by for example tray drying or dry in fluid bed.

Thus obtained granule can be by coating.The coating material that is fit to comprises that routine is used for the coating material of coated tablet, granule etc.In preferred embodiments, coating is water miscible.In another preferred embodiment, coating is that gastric juice is stable and be dissolved in intestinal juice.

Peroral dosage form of the present invention can also comprise the excipient of the routine of the definite character that depends on preparation except can comprising The compounds of this invention and at least a retarding agent and at least a disintegrating agent.The categories of excipients that is fit to comprises filler, lubricant, film coating agent, binding agent, fluidizer, solubilizing agent and surfactant.

Document for example disclosed excipient among LdH or the HoPE (content of document is incorporated in this description as a reference) can be applied in the pharmaceutical composition of the present invention.What excipient accounted for total composition weight usually is no more than 50%, preferably is no more than 40%, and more preferably 35%.

The example of the filler that is fit to is a microcrystalline Cellulose, and it preferably is present in the pharmaceutical composition of the present invention.The example comprises Avicel ^(FMC), Avicel for example ^PH101,102,105, RC581 or RC591 (LdH, 216 pages), Emcocel ^(Mendell Corp.), Elcema ^(Degussa), Filtrak ^, Heweten ^And Pharmacel ^Preferably, the weight ratio of microcrystalline Cellulose and The compounds of this invention is from about 1: 8 to about 1: 14, more preferably from about 1: 10 to about 1: 12.

The example of the disintegrating agent that is fit to comprises: (i) native starch, as corn starch, potato starch etc., directly can press starch, as Sta-rx ^1500, modified starch, as carboxymethyl starch and carboxymethyl starch sodium, it can Primojel ^, Explotab ^And Expiosol ^Form obtain, and starch derivatives is as amylose; (ii) cross-linking sodium carboxymethyl cellulose is as Ac-di-sol ^, Primellose ^, Pharmacel ^XL, Explocel ^And Nymcel ^ZSX; (iii) alginic acid and alginate are as sodium alginate; (iv) methacrylic acid-divinyl benzene copolymer salt is as Amberlite ^IRP-88; (v) vinylpyrrolidone polymer, as crospolyvinylpyrrolidone, polyvinylpolypyrrolidone for example, Polyplasdone ^XL (LdH, 1245 pages) and Kollidon ^CL; (vi) aluminium-magnesium silicate and Bentonite.In the preferred embodiment of the invention, use native starch, as corn starch and/or cross-linking sodium carboxymethyl cellulose.

The example of the fluidizer that is fit to comprises: silicon dioxide, colloidal silica is as Aerosil 200 (LdH, 117 pages), magnesium trisilicate, Powderd cellulose, starch, Pulvis Talci and calcium phosphate.Colloidal silica preferably is present in the pharmaceutical composition of the present invention as Aerosil 200.

The example of the lubricant that is fit to comprises: stearic acid, magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, Polyethylene Glycol, sodium benzoate, sodium lauryl sulphate (LdH, 517 pages), mineral oil and polyoxyethylene monostearate.Combination that also can be with lubricator.Magnesium stearate preferably is present in the pharmaceutical composition of the present invention.

The example of the surfactant that is fit to comprises: alkyl sulfate, as lauryl sulfate, for example potassium, magnesium or be preferably the lauryl sulfate of sodium are as Duponol ^C (LdH, 517 pages), tetradecyl sulfate, cetyl sulfate or octadecyl sulfate; Fatty acid polyhydroxy alkyl ester type non-ionic surface active agent is as sorbitan monolaurate, dehydrating sorbitol monooleate, anhydrosorbitol monostearate, sorbitan-monopalmityl ester, anhydrosorbitol tristearate or anhydrosorbitol trioleate; The polyoxyethylene adduct of fatty acid polyhydroxy alkyl ester is as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan tristearate or polyoxyethylene sorbitan trioleate; Cithrol is as Myrj 45, PEG400 stearate or Macrogol 2000 stearate; Phospholipid is as lecithin; Arabic gum, tragakanta; The ethylating fat of polyoxy, the ethylating triglyceride oleate of polyoxy (oleotriglycerides), linolizated triglyceride; The polyethylene oxide condensation compound of aliphatic alcohol, alkyl phenol or fatty acid or 1-methyl-3-(2-ethoxy)-imidazolidine-2-alkane.Term " polyoxy is ethylating " is meant that the material of being discussed comprises polyoxyethylene chain, and the degree of polymerization is usually between 2-40, particularly between 10-20.Be preferably alkyl sulfate.

Peroral dosage form of the present invention can be united with quick-release systems.Associating can be the double-layer tablet that comprises quick-release systems and have the matrix system of sustained release property.Double-layer tablet can comprise the The compounds of this invention of two kinds of dosage, and as licarbazepine, a part is fit to sustained-release dosage is provided and another part is fit to provide rapid release dosage.For the tablet that comprises licarbazepine, " rapid release " be meant under external licarbazepine test leaching condition of the present invention, discharges at least in 0.5 hour in 90% and 1.5 hour of dosage and discharge 100% of dosage.

In one embodiment of the invention, advantageous applications 500mg licarbazepine dose.

In addition, the present invention relates to:

● the disintegrating tablet that contains controlled release granule that be administered once suitable every day, described controlled release granule comprise licarbazepine and at least a polymer as retarding agent; Particularly wherein said at least a polymer is selected from the disintegrating tablet of polymethacrylates, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose.This disintegrating tablet does not preferably have food effect.

● comprise the oral controlled release medicine composition of licarbazepine, it is showing maintenance level between about 4 and 25 hours after administration.

● the oral administration licarbazepine is with the method for treatment affective disorder, and described method comprises and is administered orally in the patient who needs licarbazepine therapy peroral dosage form of the present invention once a day.

Only by way of example preferred compositions of the present invention and method are described below.

Initialism

The Ac acetyl group

Aqu. aqueous

Dansyl 5-(dimethylamino)-1-naphthalene sulfonyl base

The Et ethyl

The HPLC high pressure liquid chromatography

The Me methyl

The NMR nuclear magnetic resonance, NMR

RT or rt room temperature

The THF oxolane

The Ts tosyl

Embodiment 1: the disintegrating tablet that comprises licarbazepine in controlled release granule

Every contains 500mg medicine (thick medicine: x ₅₀=220 μ m)

A) (sheet is heavy: 790mg) for tablet composition

Component (mg)

Licarbazepine 500.00

Eudragit?E30D 100.00

Ethyl cellulose, aqueous dispersion 35.00

Microcrystalline Cellulose 45.00

Cross-linking sodium carboxymethyl cellulose 40.00

Starch Sta-rx ^62.50

Aerosil?200 3.75

Magnesium stearate 3.75

B) preparation method

Licarbazepine is used dispersion spray granulation in fluidized bed dryer (Aeromatic Fielder MP1) of Eufragit E30D and ethyl cellulose.Count the Frewitt mill screening of 1mm with particle drying and with being equipped with order.Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, starch and Aerosil 200 also are sized and join in the granule.Mixture mixes with blending bin (Turbula).Magnesium stearate also also adds by manual sieve (order is counted 0.8mm) screening.Last mixture mixes with blending bin (Turbula) and with Korsch PH 250 tablet machine tablettings.Sheet is ellipse, curve, and 18mm grows, wide and disconnected stricture of vagina (the sheet weight: 790mg) of 7.1mm.

Embodiment 2: with the similar method of embodiment 1 described method in, also can prepare the disintegrating tablet that in controlled release granule, comprises licarbazepine, wherein every comprises 750mg, 250mg or 125mg medicine.

Embodiment 3:10-oxo-10, the enantioselectivity transfer hydrogenation of 11-dihydro-dibenzo [b, f] azepine -5-benzoic acid amides generates R (-)-10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide

To 10-oxo-10, and 11-dihydro-dibenzo [b, f] azepine -5-benzoic acid amides (300mg, 1.189mmol) and RuCl[(1R, 2R)-right-TsNCH (C ₆H ₅) CH (C ₆H ₅) NH ₂] (η ⁶-right-cymol), Aldrich, Switzerland) (8.8mg, the CH of mixture 0.0138mmol) ₂Cl ₂(15mL) drip formic acid and NEt down at 23 ℃ in the solution ₃(5: 2,328mg: aqueous premix 289mg) also stirred 10 minutes.With clear solutions reflux 16 hours.Reactant mixture is cooled to room temperature, uses CH ₂Cl ₂(20mL) dilute and use NaHCO ₃The aqueous solution neutralization.After the salt water washing, solution under reduced pressure concentrates.Residue is that eluant carry out purification obtain R (-)-10 with 6: 1 EtOAc-MeOH mixture with flash chromatography on silicagel column, 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide (enantiomeric purity (ee)＞99%, on Chiracel OD, determine retention time 9.46 minutes by HPLC).[α] _D ^Rt=-195.3 ° (ethanol). ¹H-NMR(400MHz，CDCl ₃)：7.70-7.20(m，8H)，5.30(br?s，1H)，5.10-4.60(br?s，2H)，3.75-3.40(m，1H)，3.20-2.90(m，1H)，2.50(br?s，2H)。NMR data refer document: Benes, people such as J.., J.Med.Chem.1999,42,2582-2587.Molecular weight: 254.291.

Embodiment 4:10-oxo-10, the enantioselectivity transfer hydrogenation of 11-dihydro-dibenzo [b, f] azepine -5-benzoic acid amides generates S (+)-10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide

To 10-oxo-10, and 11-dihydro-dibenzo [b, f] azepine -5-benzoic acid amides (300mg, 1.189mmol) and RuCl[(1S, 2S)-right-TsNCH (C ₆H ₅) CH (C ₆H ₅) NH ₂] (η ⁶-right-cymol) (11mg, the CH of mixture 0.0173mmol) ₂Cl ₂(15mL) add formic acid and NEt at 23 ℃ of following minute two parts in the solution ₃(5: 2,656mg: aqueous premix 578mg) also stirred 10 minutes.Add formic acid (50 μ L) afterwards and with clear solutions reflux 16 hours.Reactant mixture is cooled to room temperature, uses CH ₂Cl ₂(20mL) dilute and use NaHCO ₃The aqueous solution neutralization.After the salt water washing, solution under reduced pressure concentrates.Residue is that eluant carry out purification obtain S (+)-10 with 6: 1 EtOAc-MeOH mixture with flash chromatography on silicagel column, 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide (ee＞99%, on ChiracelOD, determine retention time 12.00 minutes by HPLC).[α] _D ^Rt=+196.6 ° (ethanol). ¹H-NMR(400MHz，CDCl ₃)：7.70-7.20(m，8H)，5.30(br?s，1H)，5.10-4.60(br?s，2H)，3.75-3.40(m，1H)，3.20-2.90(m，1H)，2.50(br?s，2H)。NMR data refer document: Benes, people such as J.., J.Med.Chem.1999,42,2582-2587.Molecular weight: 254.291.Another kind method:

To 10-oxo-10, and 11-dihydro-dibenzo [b, f] azepine -5-benzoic acid amides (300mg, 1.189mmol) and RuCl[(1S, 2S)-right-dansylNCH (C ₆H ₅) CH (C ₆H ₅) NH ₂] (η ⁶-right-cymol) (8.5mg, the CH of mixture 0.012mmol) ₂Cl ₂(15mL) drip formic acid and NEt down at 23 ℃ in the solution ₃(5: 2,328mg: aqueous premix 289mg) also stirred 10 minutes.With clear solutions reflux 16 hours.Reactant mixture is cooled to room temperature, uses CH ₂Cl ₂(20mL) dilute and use NaHCO ₃The aqueous solution neutralization.After the salt water washing, solution under reduced pressure concentrates.Residue is that eluant carry out purification obtain S (+)-10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide with 6: 1 EtOAc-MeOH mixture with flash chromatography on silicagel column.

Embodiment 5:RuCl[(1S, 2S)-right-dansylNCH (C ₆H ₅) CH (C ₆H ₅) NH ₂] (η ⁶-right-cymol)

A) (S, S)-5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenyl-ethyl)-amide

To (S, S)-(250mg 1.2mmol) and in the THF solution of triethylamine (0.5mL) drips dansyl chloride (318mg, THF 1.2mmol) (2mL) solution at 0 ℃ to diphenyl ethylene diamine.At room temperature stir after 16 hours in vacuum to go down to desolventize and residue heavily is dissolved in the dichloromethane (20mL).Organic solution NaHCO ₃Na is used in solution (5mL) washing ₂SO ₄Drying, and after filtration with removal of solvents.Separate through flash chromatography and to obtain (S S)-5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenyl-ethyl)-amide, is yellow oil, with it by the vacuum drying crystallization.Molecular weight: 445.59. ¹H-NMR(400MHz，CDCl ₃)：8.36(t，J＝7.5Hz，2H)，8.17(dd，J＝7.2Hz，1.2Hz，1H)，7.47(dd，J＝8.8Hz，1H)，7.34(dd，J＝8.5Hz，1H)，7.24-7.16(m，4H)，7.11(d，J＝7.5Hz，1H)，6.99-6.74(m，6H)，4.61(d，J＝8.5Hz，1H)，4.20(d，J＝8.5Hz，1H)，2.80(s，6H)。

B) RuCl[(1S, 2S)-right-dansylNCH (C ₆H ₅) CH (C ₆H ₅) NH ₂] (η ⁶-right-cymol)

Will (S, S)-5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-1,2-diphenyl-ethyl)-amide (80mg, 0.18mmol), NEt ₃(36mg is 0.36mmol) with [RuCl ₂(right-cymol)] ₂(55mg, 2-propanol solution 0.09mmol) was 80 ℃ of heating 1 hour.Wash then with removal of solvents, and with wine-colored residue water (2mL).Solid is dry and need not any purification and directly use under vacuum.Molecular weight: 715.34.

Claims (20)

1. comprise 10, the oral controlled release medicine composition of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide.

2. pharmaceutical composition according to claim 1, it is to contain to comprise 10, the disintegrating tablet of the controlled release granule of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide.

3. pharmaceutical composition according to claim 2, wherein 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide is present in the granule with the content of the 60-90% that accounts for controlled release granule weight.

4. according to claim 2 or 3 described pharmaceutical compositions, it comprises, and to have median particle size be 10 of 150-300 μ m, 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide.

5. according to any described pharmaceutical composition among the claim 2-4, wherein controlled release granule comprises at least a polymer of polymethacrylates, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose that is selected from as retarding agent.

6. pharmaceutical composition according to claim 5, it comprises polymethacrylates and ethyl cellulose, and wherein polymethacrylates is present in the granule with the content of the 5-25% that accounts for controlled release granule weight.

7. according to claim 5 or 6 described pharmaceutical compositions, it comprises polymethacrylates and ethyl cellulose, and wherein ethyl cellulose is present in the granule with the content of the 2-10% that accounts for controlled release granule weight.

8. according to any described pharmaceutical composition among the claim 1-7, it comprises 10 of the 50-80% that accounts for composition total weight, 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide.

9. according to any described pharmaceutical composition among the claim 1-8, it comprises microcrystalline Cellulose.

10. according to any described pharmaceutical composition among the claim 1-9, it comprises at least a native starch as disintegrating agent.

11. pharmaceutical composition according to claim 10, it comprises corn starch as disintegrating agent.

12. comprise 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] oral controlled release medicine composition of azepine -5-Methanamide, wherein in use, 70-90% is described 10, and 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide discharged in 6 hours, for the dosage form of 500mg, this confirms by dissolution test outside the standard body in the time of 37 ℃, in the phosphate buffer of pH about 6.8.

13. according to claim 12ly comprise 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] oral controlled release medicine composition of azepine -5-Methanamide, wherein in use, 80-90% is described 10, and 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide discharged in 6 hours, for the dosage form of 500mg, this confirms by dissolution test outside the standard body in the time of 37 ℃, in the phosphate buffer of pH about 6.8.

14. according to any described oral controlled release medicine composition among the claim 1-13, it does not have food effect.

15. the disintegrating tablet that contains controlled release granule that be administered once suitable every day, described controlled release granule comprises 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide and at least a polymer as retarding agent.

16. disintegrating tablet according to claim 15, wherein said at least a polymer is selected from polymethacrylates, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and methylcellulose.

17. according to claim 15 or 16 described disintegrating tablets, it does not have food effect.

18. comprise 10, the oral controlled release medicine composition of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide, it is showing maintenance level between about 4 and 25 hours after administration.

19. according to claim 1-18 any one defined 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide and excipient adjuvant are used for the treatment of purposes in the medicine of patients with affective disorders in preparation.

20. oral administration 10,11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide with the treatment affective disorder method, described method comprises and is administered orally in needs 10, the patient of 11-dihydro-10-hydroxyl-5H-dibenzo [b, f] azepine -5-Methanamide treatment is once a day according to any described pharmaceutical composition of claim 1-18.