CN105377840B

CN105377840B - The salt and its crystal formation and amorphous article of a kind of diazepan compounds

Info

Publication number: CN105377840B
Application number: CN201480032674.8A
Authority: CN
Inventors: 宋小叶; 劳海萍; 盛晓霞; 盛晓红
Original assignee: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
Current assignee: Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd
Priority date: 2014-05-28
Filing date: 2014-05-28
Publication date: 2017-12-22
Anticipated expiration: 2034-05-28
Also published as: CN105377840A; WO2015180060A1

Abstract

The salt and its crystal formation and amorphous article of a kind of diazepan compounds are disclosed, it has in the dissolution rate etc. of dissolubility, stability, solid pharmaceutical preparation and improve characteristic；Also disclose the preparation method, its pharmaceutical composition and its nerve and the purposes of psychiatric disorders and the medicine of disease relevant with orexin receptor for preparing treatment or prevention of the salt and its crystal formation and amorphous article.

Description

The salt and its crystal formation and amorphous article of a kind of diazepan compounds

Technical field

The present invention relates to pharmaceutical chemistry crystallization technique field.A kind of in particular it relates to diazepan compounds MK- 4305 salt and its crystal formation and amorphous article, further relate to preparation method, its medicine group of the salt and its crystal formation and amorphous article Compound and the purposes as orexin receptor antagonists.

Background technology

MK-4305 (English name Suvorexant) is a kind of new orexin of Mo Shadong drugmakers research and development (hypocretins) receptor antagonist, for treat or prevent the nerve relevant with orexin receptor and psychiatric disorders and Disease, the medicine for class sleep-disorder of being had a sleepless night especially as treatment.MK-4305 is intended to help to maintain in brain clearly by blocking Awake neurotransmitter, to promote to sleep.III clinical trial phase data are shown, compared with placebo, the medicine, which is used to treat, to be lost Sleep, the sleep for improving insomniac is maintained and sleep generation is evident in efficacy.The formulation of MK-4305 clinical tests is tablet, dosage 10 milligrams~80 milligrams.

MK-4305 is a kind of diazepan compounds, and chemical name is the chloro- 2- of 5- { (5R) -5- methyl -4- [5- first Base -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane -1- bases } -1,3- benzoxazoles, molecular formula For C₂₃H₂₃ClN₆O₂；Molecular weight is 450.9；Chemical structural formula is as follows：

Patent document WO2008/069997A1 discloses MK-4305 and its production and use.

Patent document WO2012/148553A1 discloses MK-4305 anhydrous crystal forms I, anhydrous crystal forms II and its preparation side Method, and disclose its X-ray diffractogram (XRD), Differential scanning calorimetry figure (DSC) and¹³C- solid state nmrs wave spectrum (¹³C- NMR characterize data).Both anhydrous crystal forms are Mutual Variety Relationships, anhydrous crystal forms I when mutual temperature is 35~40 DEG C ,≤35 DEG C It is the most stable of crystal formation of thermodynamics, anhydrous crystal forms II is thermodynamics most stable of crystal formation at >=40 DEG C.

The present inventor, which studies, to be found：Above-mentioned MK-4305 anhydrous crystal forms I and anhydrous crystal forms II is hydrophobicity, in water Solubility extreme difference, in the pharmaceutical dosage form for not being suitable for having higher intrinsic solubility requirement.In addition, both anhydrous crystal forms is mutual It is also to influence the unfavorable factor of formulation development to become characteristic.Therefore, this area stills need to develop new MK-4305 or the crystal formation of its salt Or amorphous article.

The content of the invention

In view of the shortcomings of the prior art, it is an object of the invention to provide new MK-4305 salt and its crystal formation and without fixed Type thing, and their preparation method, pharmaceutical composition and purposes.

Compared with known MK-4305 and its crystal formation, MK-4305 salt and its crystal formation provided by the invention should with amorphous article With one or more more superior performances, such as：Stability well include stability of crystal form, thermal stability, chemical stability, Mechanical stability, bin stability etc.；Dissolubility is good；Dissolution rate is fast；Crystallinity is high；It is not easy moisture absorption；It is easy to purify and handles； Chemical purity is high；Low-residual solvent；Hypotoxicity；Granule-morphology is good；It is suitable preparation machinability such as good fluidity, favourable Powder viscosity, tight ness rating and rammability；It is apparent to improve preparation；Improve bioavilability and drug effect；Extend storage life；It is adapted to system Agent novel form application etc., particularly have in solubility, dissolution velocity, stability of crystal form, bin stability etc. excellent Gesture performance.

According to the purpose of the present invention, the present invention provides MK-4305 hydrochlorides and its crystal formation and amorphous article, MK-4305 sulphur Hydrochlorate and MK-4305 phosphate, and their preparation method, pharmaceutical composition and purposes.

According to the purpose of the present invention, the present invention provides MK-4305 hydrochlorides, and its structural formula is as follows：

HPLC, which is characterized, to be shown, the actual content of MK-4305 free alkalis is 92.1% in MK-4305 hydrochlorides, theoretical content For 92.5%.Testing result shows：The MK-4305 hydrochlorides are the changes that MK-4305 and hydrogen chloride are formed with about 1: 1 mol ratio Compound.

According to the purpose of the present invention, the present invention provides the preparation method of MK-4305 hydrochlorides, and methods described includes following step Suddenly：In the solvent selected from water, alcohol or its mixture, by MK-4305 that mol ratio is 1: 1~1: 2 and mixed in hydrochloric acid and react, Solvent is removed after the completion of reaction, obtains the MK-4305 hydrochlorides.

Preferably, the solvent is selected from water, ethanol or its mixture.

Preferably, the temperature of the reaction is 10~50 DEG C, and the time of the reaction is 1~24 hour.

" the removing solvent " can use the ordinary skill in the art to complete, such as filter, centrifuge or be spin-dried for；It is preferred that Ground, solvent is removed using the method that is spin-dried for；The method that is spin-dried for is usually to be rotated with the pressure less than atmospheric pressure, and preferably pressure is less than 0.09MPa；It is highly preferred that the temperature for being spin-dried for method is 10~50 DEG C.

Preferably, the solution that hydrochloric acid or hydrochloric acid are formed in the solvent is added to MK-4305 shapes in the solvent Into solution or suspension in.

" hydrochloric acid " is the aqueous solution of hydrogen chloride, concentration 37% (percentage by weight), from commercially available.

The method that initiation material MK-4305 can refer to patent document WO2008069997A1 reaction schemes G descriptions is prepared into Arrive, the document is incorporated into the application by way of quoting its full text.

The MK-4305 hydrochlorides of the present invention have following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), the MK-4305 hydrochlorides of the invention solubility in water at 25 DEG C More known MK-4305 solubility is high, illustrates the MK-4305 hydrochlorides of the present invention and has more preferable solubilizing effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochlorides of the present invention has more High dissolution rate and dissolution rate, thus there is more preferable bioavilability.

According to the purpose of the present invention, the crystal formation I that the present invention provides MK-4305 hydrochlorides (is referred to as " crystal formation in the present invention I "), radiated using Cu-K α, the crystal formation I has spy with the X-ray powder diffraction collection that the θ of the angle of diffraction 2 is represented in following position Levy peak：6.6 ± 0.2 °, 9.4 ± 0.2 °, 11.0 ± 0.2 °, 12.8 ± 0.2 °, 14.1 ± 0.2 ° and 16.0 ± 0.2 °.

In a currently preferred embodiment, radiated using Cu-K α, the crystal formation I is represented with the θ of the angle of diffraction 2 X-ray powder diffraction collection has characteristic peak in following position：6.6±0.2°、9.4±0.2°、11.0±0.2°、12.8± 0.2°、14.1±0.2°、16.0±0.2°、17.9±0.2°、18.8±0.2°、20.0±0.2°、22.2±0.2°、25.0± 0.2 ° and 26.0 ± 0.2 °.

In a further preferred embodiment of the invention, radiated using Cu-K α, the crystal formation I is with the θ of the angle of diffraction 2 The X-ray powder diffraction collection of expression has characteristic peak and its relative intensity in following position：

Without limitation, a representative instance of the crystal formation I has X-ray powder diffraction figure as shown in Figure 1.

The FTIR spectrum of the crystal formation I wave number be 1700,1632,1508,1454,1414,1349,1304, 1268th, 1179,1082,1055,951,884,814 and 704cm^-1Place has characteristic peak.

According to the purpose of the present invention, the present invention provides MK-4305 hydrochloride Forms I preparation method, and it includes following step Suddenly：By MK-4305 hydrochlorides in C₄~C₆Suspension is formed in ether, stirring and crystallizing, by the crystal separation of precipitation, dries, obtains institute State MK-4305 hydrochloride Forms I.

The C₄~C₆Ether can be ether, ethyl propyl ether, methyl tertiary butyl ether(MTBE), tert amyl methyl ether(TAME), propyl ether, isopropyl Ether；Preferably, the C₄~C₆Ether is selected from ether, isopropyl ether, methyl tertiary butyl ether(MTBE) or its mixture；It is highly preferred that the C₄~ C₆Ether is ether.

Preferably, the operation temperature of the preparation method is room temperature.

Preferably, in the suspension MK-4305 hydrochlorides dosage be operation temperature under its in the C₄~C₆It is molten in ether 2~10 times of Xie Du, more preferably 2~5 times.

Preferably, the time of the crystallization is 12~36 hours, more preferably 12~24 hours.

Preferably, the temperature of the drying is 10~60 DEG C, more preferably 10~40 DEG C.

Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.

Above-mentioned crystal formation I preparation method employs the crystallization mode of magma, is (to have the supersaturated solution of sample insoluble Solid presence) stirring and crystallizing, obtain required crystal.

The MK-4305 hydrochloride Forms I of the present invention has following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), MK-4305 hydrochloride Forms I of the invention is at 25 DEG C in water The more known MK-4305 of solubility solubility is high, illustrates the MK-4305 hydrochloride Forms I of the present invention and has preferably solubilising Effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochloride Forms I of the present invention With higher dissolution rate and dissolution rate, thus there is more preferable bioavilability.

3. the present invention MK-4305 hydrochloride Forms I room temperature, relative humidity 10%~90% drier in place 4 Individual month, its crystal formation and fusing point were all constant.Illustrate the bin stability that the MK-4305 hydrochloride Forms I of the present invention has had, favorably In adapt to manufacture, storage, transport various environmental conditions, can preferably resist manufacture, storage, transport etc. during by when Between, the problems such as activity substance content caused by the factor such as humidity is uneven, purity declines, preparation machinability reduces, reduce Thus the effect of bringing downside risk and security risk.

According to the purpose of the present invention, the crystal formation II that the present invention provides MK-4305 hydrochlorides (is referred to as " brilliant in the present invention Type II "), radiated using Cu-K α, the X-ray powder diffraction figure that the crystal formation II is represented with the θ of the angle of diffraction 2 is at 16.5 ± 0.2 ° With characteristic peak.

Without limitation, a representative instance of the crystal formation II has X-ray powder diffraction figure as shown in Figure 3.

The FTIR spectrum of the crystal formation II wave number be 1695,1631,1468,1414,1371,1260,1215, 1158th, 1057,952,924,878,810,770 and 695cm^-1Place has characteristic peak.

According to the purpose of the present invention, the present invention provides MK-4305 hydrochloride Forms II preparation method, and it includes following step Suddenly：MK-4305 hydrochlorides are formed into suspension in organic solvent, wherein the organic solvent is selected from C₄~C₅Ester, C₃~C₄ Ketone, normal heptane or its mixture, stirring and crystallizing, by the crystal separation of precipitation, dry, obtain the crystal formation II.

The C₄~C₅Ester can be ethyl acetate, isopropyl acetate, propyl acetate, ethyl propionate or isopropyl acetoacetic ester；Institute State C₃~C₄Ketone can be acetone or butanone.

Preferably, the organic solvent is selected from acetone, butanone, ethyl acetate, isopropyl acetate or normal heptane.

Preferably, in the suspension MK-4305 hydrochlorides dosage be operation temperature under its in the organic solvent 2~10 times of solubility, more preferably 2~5 times.

Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.

Above-mentioned crystal formation II preparation method employs the crystallization mode of magma, is (to have the supersaturated solution of sample insoluble Solve solid presence) stirring and crystallizing, obtain required crystal.

The MK-4305 hydrochloride Forms II of the present invention has following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), MK-4305 hydrochloride Forms II of the invention is at 25 DEG C in water The more known MK-4305 of solubility solubility is high, illustrates the MK-4305 hydrochloride Forms II of the present invention and has preferably solubilising Effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochloride Forms II of the present invention With higher dissolution rate and dissolution rate, thus there is more preferable bioavilability.

3. the present invention MK-4305 hydrochloride Forms II room temperature, 10%~90%RH of relative humidity drier in put Put 4 months, its crystal formation and fusing point are all constant.Illustrate the bin stability that the MK-4305 hydrochloride Forms II of the present invention has had, Be advantageous to adapt to manufacture, storage, the various environmental conditions of transport, can preferably resist during manufacture, storage, transport etc. As the problems such as the activity substance content caused by the factors such as time, humidity is uneven, purity declines, preparation machinability reduces, The effect of thus reduction is brought downside risk and security risk.

According to the purpose of the present invention, the amorphous article that the present invention provides MK-4305 hydrochlorides (is referred to as in the present invention " amorphous article ").

Without limitation, a representative instance of the amorphous article has X-ray powder diffraction figure as shown in Figure 5.

The FTIR spectrum of the amorphous article wave number be 1698,1627,1505,1450,1413,1350, 1279th, 1172,1109,1055,961,824,778 and 702cm^-1Place has characteristic peak.

According to the purpose of the present invention, the present invention provides the preparation method of MK-4305 hydrochloride amorphous articles, and it includes following Step：MK-4305 hydrochlorides are formed into suspension in a solvent and stirred, wherein the solvent is selected from water, C₁~C₄Alcohol or it is mixed Compound, by the solid separation of precipitation, dry, obtain the MK-4305 hydrochlorides amorphous article.

The C₁~C₄Alcohol can be methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol.

Preferably, the solvent is selected from methanol, ethanol or water.

Preferably, the operation temperature of the preparation method is 10~30 DEG C.

Preferably, the dosage of MK-4305 hydrochlorides is that it dissolves in the solvent under operation temperature in the suspension 2~10 times, more preferably 2~5 times of degree.

Preferably, the time of the stirring is 12~36 hours, more preferably 12~24 hours.

Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.

The preparation method of above-mentioned amorphous article employs the crystallization mode of mashing, is (to have the supersaturated solution of sample not Dissolved solid presence) stir in a solvent, obtain required amorphous article.

The MK-4305 hydrochloride amorphous articles of the present invention have following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), the MK-4305 hydrochlorides amorphous article of the invention water at 25 DEG C The middle more known MK-4305 of solubility solubility is high, illustrates the MK-4305 hydrochlorides amorphous article of the present invention and has preferably Solubilizing effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid system containing MK-4305 hydrochlorides amorphous article of the present invention Agent has higher dissolution rate and dissolution rate, thus has more preferable bioavilability.

3. the present invention MK-4305 hydrochlorides amorphous article room temperature, 10%~90%RH of relative humidity drier in Place 4 months, its XRD spectrum is constant.Illustrate the bin stability that the MK-4305 hydrochloride amorphous articles of the present invention have had, Be advantageous to adapt to manufacture, storage, the various environmental conditions of transport, can preferably resist during manufacture, storage, transport etc. As the problems such as the activity substance content caused by the factors such as time, humidity is uneven, purity declines, preparation machinability reduces, The effect of thus reduction is brought downside risk and security risk.

The crystal formation I of MK-4305 hydrochlorides of the present invention, crystal formation II, amorphous article any preparation method in：

Indicated except no special, " room temperature " refers to 10~30 DEG C of temperature.

" stirring ", the conventional method of this area can be used to complete, agitating mode such as magnetic agitation, mechanical agitation It it is 50~1800 revs/min, preferably 300~900 revs/min Deng, mixing speed." separation ", the normal of this area can be used Rule technology is completed, such as filtering, centrifugation etc..The filtering is usually to be filtered at room temperature with the pressure less than atmospheric pressure, It is preferred that pressure is less than 0.09MPa.The concrete operations of the centrifugation are：The sample for being intended to separation is placed in 2 milliliters of centrifuge tubes, with 6000 revs/min of speed is centrifuged, until solid is all sink to centrifugation bottom of the tube.

Alternatively, the crystal formation or amorphous article that are obtained after " separation " are washed, wash solvent used preferably with crystalline substance Solvent used is identical in the preparation method of type or amorphous article, and the dosage of cleaning solvent is generally the system of crystal formation or amorphous article 0.3~1 times of solvent volume used in Preparation Method.

" drying ", the ordinary skill in the art can be used to complete, such as air drying, forced air drying or decompression are dry Dry, drying equipment is fume hood, convection oven or vacuum drying oven；It can be carried out in the case where depressurizing or not depressurizing, preferably pressure is small In 0.09Mpa.

According to the purpose of the present invention, the present invention provides MK-4305 sulfate, and its structural formula is as follows：

HPLC, which is characterized, to be shown, the actual content of MK-4305 free alkalis is 90.2% in MK-4305 sulfate, theoretical content For 90.0%.Testing result shows：The MK-4305 sulfate is the chemical combination that MK-4305 and sulfuric acid are formed with about 2: 1 mol ratios Thing.

The FTIR spectrum of the MK-4305 sulfate wave number be 1696,1635,1621,1573,1505, 1451st, 1412,1342,1263,1179,1042,881,822 and 786cm^-1Place has characteristic peak.

According to the purpose of the present invention, the present invention provides the preparation method of MK-4305 sulfate, and methods described includes following step Suddenly：In the solvent selected from water, alcohol or its mixture, MK-4305 and sulfuric acid that mol ratio is 2: 1~1: 1 are mixed and reacted, Solvent is removed after the completion of reaction, obtains the MK-4305 sulfate.

Preferably, the solvent is selected from water, methanol, ethanol or its mixture.

Preferably, solvent is removed using the method that is spin-dried for；The method that is spin-dried for is usually to be rotated with the pressure less than atmospheric pressure, It is preferred that pressure is less than 0.09MPa；It is highly preferred that the temperature for being spin-dried for method is 10~50 DEG C.

Preferably, the solution that sulfuric acid or sulfuric acid are formed in the solvent is added to MK-4305 shapes in the solvent Into solution or suspension in.

" sulfuric acid ", is the aqueous solution of sulfuric acid, concentration 98% (percentage by weight), from commercially available.

The MK-4305 sulfate of the present invention has following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), the MK-4305 sulfate of the invention solubility in water at 25 DEG C More known MK-4305 solubility is high, illustrates the MK-4305 sulfate of the present invention and has more preferable solubilizing effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 sulfate of the present invention has more High dissolution rate and dissolution rate, thus there is more preferable bioavilability.

According to the purpose of the present invention, the present invention provides MK-4305 phosphate, and its structural formula is as follows：

HPLC, which is characterized, to be shown, the actual content of MK-4305 free alkalis is 93.2% in MK-4305 phosphate, theoretical content For 93.5%.Testing result shows：The MK-4305 phosphate is the chemical combination that MK-4305 and phosphoric acid are formed with about 3: 1 mol ratios Thing.

The phosphatic FTIR spectrums of MK-4305 wave number be 1634,1572,1506,1452,1409, 1375th, 1260,1179,990,952,922,881,823 and 726cm^-1Place has characteristic peak.

According to the purpose of the present invention, the present invention provides MK-4305 method for production of phosphate salt, and methods described includes following step Suddenly：In the solvent selected from water, alcohol or its mixture, MK-4305 and phosphoric acid that mol ratio is 3: 1~1: 1 are mixed and reacted, Solvent is removed after the completion of reaction, obtains the MK-4305 phosphate；

Preferably, the solution that phosphoric acid or phosphoric acid are formed in the solvent is added to MK-4305 shapes in the solvent Into solution or suspension in.

" phosphoric acid " is the aqueous solution of phosphoric acid, concentration 85% (percentage by weight), from commercially available.

The MK-4305 phosphate of the present invention has following beneficial property and application effect：

1. in the presence of lauryl sodium sulfate (SDS), the MK-4305 phosphate of the invention solubility in water at 25 DEG C More known MK-4305 solubility is high, illustrates the MK-4305 phosphate of the present invention and has more preferable solubilizing effect.

2. compared with the solid pharmaceutical preparation containing known MK-4305, have more containing the phosphatic solid pharmaceutical preparations of MK-4305 of the present invention High dissolution rate and dissolution rate, thus there is more preferable bioavilability.

According to the purpose of the present invention, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition include treatment and/or The crystalline substance of the MK-4305 hydrochlorides selected from the present invention of prevention effective dose, crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides Amorphous article, MK-4305 sulfate, MK-4305 phosphate or its combination of type II, MK-4305 hydrochloride, and it is at least one Pharmaceutically acceptable carrier or auxiliary agent.In addition, described pharmaceutical composition can also include other pharmaceutically useful MK-4305 or its Compound, crystal formation or the amorphous article of salt.Optionally, described pharmaceutical composition can also include it is one or more it is other can medicine Active constituents of medicine, such as sedative, hypnotic, anxiolytic, antipsychotic drug, other orexin receptor antagonists Deng.

Described pharmaceutical composition can be solid-state, semisolid or liquid, be prepared into suitable formulation as needed, pass through mouth Chamber, parenteral (such as muscle, intraperitoneal, intravenous, ICV, intracranial injection or transfusion, hypodermic injection), nose, vagina, rectum, tongue Under, the approach such as transdermal, local administration.Formulation can be solid dosage forms, such as tablet, capsule, granule, powder and pill； Liquid dosage form, such as solution, syrup, supensoid agent, dispersant and emulsion；Injectable formulation, for example, solution, dispersant, Suitable for dissolving or suspending freeze-dried in a liquid before injection；Can rectally suppository；The emulsifiable paste that can locally use, ointment, Gel, solution or suspension；The spray of inhalable administration.Formula may be adapted to quick release, the sustained release of active component Or regulation release.It can be conventional, dispersible, masticable, Orally dissolving or rapid melting preparation.The medicine Composition be preferably oral dosage form such as tablet, capsule, granule, powder, pill, more preferably tablet and capsule Agent.

Acceptable carrier or auxiliary agent in described pharmaceutical composition Chinese pharmacology, in the case of solid dosage forms, including but not It is limited to：Carrier, including starch or modified starch, sugared such as lactose, cellulose and its derivates such as powdered cellulose, crystallite are fine Dimension element, solid inorganic thing such as calcium phosphate, calcium monohydrogen phosphate, dicalcium phosphate, tricalcium phosphate, hydroxyapatite, calcium sulfate, carbonic acid Calcium, it is semi-solid such as lipid or paraffin, mannitol, sorbierite etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyethylene Pyrrolidones, microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Methylcellulose, polyethylene glycol, copolyvidone etc.；Disintegrant, for example, it is starch, sodium carboxymethyl starch, sodium starch glycollate, pre- Gelling starch, PVPP, sodium carboxymethylcellulose, Ac-Di-Sol, cataloid, alginic acid etc.；Profit Lubrication prescription, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, talcum, sodium stearyl fumarate, poly- second two Alcohol etc.；Glidant, such as cataloid, light anhydrous silicic acid, avicel cellulose, talcum powder or magnesium stearate etc.；It is compound Thing forming agent, such as the cyclodextrin and resin of various ranks；Rate of release controlling agent, such as hydroxypropyl cellulose, methylol are fine Tie up element, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc..Other available medicines Acceptable carrier or auxiliary agent include but is not limited to film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier, anti-corrosion on Agent, antioxidant etc..In oral tablet, commonly utilized carrier includes sugared such as lactose, sucrose, mannitol or sorbierite, fine Tie up cellulose product such as cornstarch, wheaten starch, gelatin, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium cellulose glycolate And polyvinylpyrrolidone, lubricant such as magnesium stearate, disintegrant such as PVPP can also be added, handed over Join sodium carboxymethylcellulose, tablet core can be further coated, such as form sugarcoating layer；In oral capsule, have Carrier or auxiliary agent include lactose, height and low molecular poly, starch, cellulose derivative, magnesium stearate, stearic acid With analog；In the case of oral soft capsule, active constituents of medicine can dissolve or be suspended in suitable liquid, such as fat Oil, atoleine or liquid macrogol；In the case of oral administration mixed suspension, active constituents of medicine mixes with emulsifying agent and suspending agent Close, sweetener and/or flavor enhancement and/or colouring agent can be added if desired, the MK-4305 of the invention in oral administration mixed suspension Hydrochloride, MK-4305 hydrochlorides crystal formation I, MK-4305 hydrochloride crystal formation II, MK-4305 hydrochloride amorphous article, MK- 4305 sulfate or MK-4305 phosphate are maintained as solid-state form as active constituents of medicine.It is every in described pharmaceutical composition A kind of carrier or auxiliary agent must be it is acceptable, can be compatible with the other compositions in formula and harmless for sufferer.

Described pharmaceutical composition can be using well known to a person skilled in the art method in the prior art to prepare.Preparing During pharmaceutical composition, MK-4305 hydrochlorides of the invention, MK-4305 hydrochlorides crystal formation I, MK-4305 hydrochloride crystal formation The amorphous article of II, MK-4305 hydrochloride, MK-4305 sulfate, MK-4305 phosphate or its combination and one or more medicines Acceptable carrier or auxiliary agent mix on, optionally, are mixed with the other drugs active component of one or more.Solid Preparation can be prepared by the technique such as directly mixing, pelletizing.Liquid preparation can by dissolve, disperse, emulsify etc. technique come Prepare.

According to the purpose of the present invention, the present invention provides the MK-4305 hydrochlorides of the present invention, the crystal formation of MK-4305 hydrochlorides I, the amorphous article of crystal formation II, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 sulfate, MK-4305 phosphate or The crystal formation II of foregoing crystal formation I or the MK-4305 hydrochloride comprising MK-4305 hydrochlorides of the present invention or MK-4305 hydrochlorides of person Or the amorphous article or MK-4305 sulfate or MK-4305 phosphate of MK-4305 hydrochlorides or the pharmaceutical composition of its combination exist Prepare for treat and/or prevent the nerve relevant with orexin receptor and psychiatric disorders and disease medicine in use On the way.

According to the purpose of the present invention, the present invention provides treatment and/or prevents the nerve and essence relevant with orexin receptor The method of godhead obstacle and disease.In a specific embodiment, the following methods of patient of needs are given：Improve sleep quality；Increase Add sleep maintenance；Increase REM sleep；Increase the sleep of 2 phases；Reduce sleep fracture；Treatment insomnia；Improve cognition；Increase memory Retain；Treatment or obesity controlling；Treatment or control are depressed；Treatment, control, improve or reduce the risk of epilepsy, including do not send out Raw epilepsy；Treatment or control pain, including neuropathic pain；Treatment or control Parkinson's；Treatment or control mental disease；Or Schizoid risk is treated, controls, improves or reduces, methods described includes giving patient's treatment of needs and/or prevention Effective dose selected from the present invention MK-4305 hydrochlorides, MK-4305 hydrochlorides crystal formation I, MK-4305 hydrochloride crystal formation II, The amorphous articles of MK-4305 hydrochlorides, MK-4305 sulfate, MK-4305 phosphate foregoing include MK- of the present invention The nothing of crystal formation II or the MK-4305 hydrochloride of crystal formation I or the MK-4305 hydrochloride of 4305 hydrochlorides or MK-4305 hydrochlorides is determined The pharmaceutical composition of type thing or MK-4305 sulfate or MK-4305 phosphate or its combination.Wherein described patient is to include people to exist Interior mammal.Under any circumstance, the active constituents of medicine given should contain sufficient amount of MK-4305, to carry For desired therapeutic effect.Selected dosage depends on desired therapeutic effect, when depending on method of administration and treating maintenance Between.Dosage will be different with patient, this depend on disease attribute and the order of severity, the body weight of patient, patient specific diet, Medicine used at the same time and those skilled in the art will be realized that other factorses.Dosage range is usually that each patient is daily about 0.5 milligram to 1.0 grams (with MK-4305 free bases), optionally, 0.5 milligram to 500 milligrams, optionally, 0.5 milligram to 200 Milligram, optionally, 5 milligrams to 50 milligrams.It can be administered in the form of single dose or multiple dose, can be administered for daily 1 to 4 times, appoint Selection of land, the administration of 1 time or 2 times is carried out daily.

The foregoing nerve relevant with orexin receptor and psychiatric disorders and disease are in following groups：Suppression It is strongly fragrant；Anxiety；Habituation；Obsession；Affective disease；Depressibility neuropathy；Dysthymic disorder；Behavioral disorder；Emotionally disturbed； Sexual dysfunction；Sexual psychology dysfunction, sexual disorder；Schizophrenia；Manic depression；Amentia；It is dull-witted；Severe intelligence Blunt and dyskinesia such as huntington disease and tourette's syndrome；Eating disorder such as apocleisis, bulimia nervosa, cachexia And obesity；Additive feeding behaviour；Carousing defaecation influent pH；Angiocardiopathy；Diabetes；Appetite the sense of taste it is disorderly；Vomiting, Nausea；Asthma；Cancer；Parkinson's disease；Cushing's syndrome disease；Basophilic adenoma；Prolactinoma；Hyperprolactinemia； Pituitary gland knurl adenoma；Hypothalamic disorder；IBD；Motility disturbances of the stomach；Gastric ulcer；Froehlich ' s syndromes；Gland Hypophysis disease；Pituitary disease；Adenohypophysis deterioration；Adenohypophysis hyperfunction；Hypothalamic adenasthenia；Kallman’ S syndromes (anosmia, hyposphresia)；Idiopathic hyperprolactinemia；The inferior colliculus cerebral disorders of growth hormone deficiency；Idiopathic Growth deficiency；Nanism；Gigantism；Acromegalia；Biology and day-night rhythm are disorderly；With disease such as neurological disorders, Sleep disordered related to restless leg syndrome of neuropathic pain；Heart and lung diseases, acute and congestive heart failure；Blood pressure mistake It is low；Hypertension；Urinary retention；Osteoporosis；Angina pectoris；Myocardial infarction；Ischemic or haemorrhagic；Subarachnoid hemorrhage；Burst Ulcer；Allergy；Benign prostatauxe；Chronic renal failure；Nephrosis；Sugared dosis tolerata reduces；Antimigraine；Hyperalgia；Pain；Carry High or exaggeration pain sensitivity such as hyperalgia, causalgia and allodynia；Acute Pain；Burn pain；It is non- Typicalness facial pain；Neuropathic pain；Backache；Complex regional pain syndrome i and II；Arthritic pain；Motion damage Wound property pain；The pain such as HIV related to infection；Pain after chemotherapy；Post-stroke pain；Postoperative pain；Neuralgia；Vomit Tell, nausea；The symptom related to visceral pain such as IBS, and angina；Antimigraine；Bladder incontinence is for example urgent Incontinence；Tolerance to anesthetic or the withdrawal to anesthetic；Sleep-disorder；Narcolepsy；Insomnia；Parasomnia；When Poor syndrome；And nerve degeneration kind obstacle include nosology on disease for example suppress releasing-dementia-parkinsonism- The compound disease of amyotrophia；Grey ball-ponto-nigral is degenerated；Epilepsy；Epileptics and other related in general orexin system Disease.

Brief description of the drawings

Fig. 1 is the crystal formation I of MK-4305 hydrochlorides of the present invention XRPD figures.

Fig. 2 is the crystal formation I of MK-4305 hydrochlorides of the present invention IR figures.

Fig. 3 is the crystal formation II of MK-4305 hydrochlorides of the present invention XRPD figures.

Fig. 4 is the crystal formation II of MK-4305 hydrochlorides of the present invention IR figures.

Fig. 5 is the XRPD figures of the amorphous article of MK-4305 hydrochlorides of the present invention.

Fig. 6 is the IR figures of the amorphous article of MK-4305 hydrochlorides of the present invention.

Fig. 7 is the IR figures of MK-4305 sulfate of the present invention.

Fig. 8 is the phosphatic IR figures of MK-4305 of the present invention.

Embodiment

The present invention with further reference to following examples, the embodiment be described in detail the crystal formation of the present invention, amorphous article and Its preparation method and application.It will be apparent for a person skilled in the art that many changes for both material and method can Implement without departing from the present invention.

Instrument and method used in gathered data：

X-ray powder diffraction (XPRD)：Used instrument is Bruker D8 Advance diffractometer, Use Ka X-ray of the copper target wavelength for 1.54nm, under 40kV and 40mA operating condition, θ -2 θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is calibrated before use with diamond dust.Sample is tested at ambient temperature, the sample that needs are detected It is placed on areflexia plate.Detailed testing conditions are as follows, angular range：3-40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.

Infrared spectrum analysis (IR) data are picked up from BrukerTensor 27, instrument control software and DAS All it is OPUS, generally use ATR equipment, in 600~4000cm^-1In the range of gather infrared absorption spectroscopy, sample and blank background Sweep time be 16 seconds, instrumental resolution 4cm^-1。

Proton nmr spectra analysis (¹HNMR) data are picked up from Bruker Ascend Tm 500.Excited, composed using full range Wide 30PPM, pulse, 30 ° of angles excite, and scan 16 times, digitized quadrature detection, temperature control 298K.

High-efficient liquid phase analysis (HPLC) data are picked up from Waters2487/2695.Using C18 chromatographic columns, 150mm × 4.6mm, 25 DEG C, wavelength 254nm of column temperature, the ml/min of flow velocity 1.0,80 microlitres of sample size, run time 15 minutes.Solvent is 0.05% trifluoroacetic acid aqueous solution: acetonitrile=1: 1, mobile phase A is 0.05% trifluoroacetic acid aqueous solution, and Mobile phase B is acetonitrile, ladder Degree is shown in Table 1.

The HPLC gradients of table 1

Time (minute)	Mobile phase A (%)	Mobile phase B (%)
			0	50	50
8	10	90
			13	10	90
13.01	50	50
			15	50	50

Organic element analysis (C, H, N, O, S) data acquisition is burnt using horizontal sample introduction in CE-400, thermal conductivity detector (TCD), Sample volume：1~5 milligram, analysis time：Analyze C, H, N, less than 5 minutes, scope：100ppm to 100%.

Various reagents used are commercially available purchase unless otherwise instructed in embodiment.

Temperature in embodiment is room temperature unless otherwise instructed.

" ultrasound " described in embodiment, can promote sample to dissolve, and concrete operations are：By the container equipped with sample suspension It is placed in ultrasonic cleaner, with 20Khz~40Khz power ultrasonic 1~60 minute.Unless otherwise instructed, typically with 40Khz Power ultrasonic 5 minutes.

Preparation example 1

The preparation of MK-4305 free alkalis can be according to the method described by WO2008/069997A1 reaction schemes G, wherein institute The compound used can be prepared according to the method described by WO2008/069997A1.Specially：

To 22.3 grams of (5R) -5- methyl isophthalic acids, hydrochloride, the 15.9 grams of 2- (2H- of 4- Diazesuberane -1- benzyl formates 1,2,3-triazoles -2- bases) -5- methyl benzoic acids, 12.8 grams of 1- hydroxyls -7- azacyclo-s BTAs and 43.1 milliliters of N- methyl Quinoline adds 22.5 grams of N- (3- dimethylaminopropyls) in the solution in 300 milliliters of DMFs, and will reaction It is stirred at room temperature overnight, reacts and distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution, with water, salt water washing, use sulphur Sour magnesium is dried, and is concentrated via rotary evaporation, and residue obtains colourless via silica gel chromatography (ethyl acetate/hexane) Jelly (5R) -5- methyl -4- [5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane - 1- benzyl formates.

29.6 grams of (5R) -5- methyl -4- [5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl] -1 will be contained, Solution of the 4- Diazesuberane -1- benzyl formates in 300 milliliters of ethyl acetate and 200 ml methanols is placed in flask, is subtracted Pressure vacuumizes, and with nitrogen purging three times.2.4 gram of 20% palladium dydroxide on carbon is added into flask.Flask is subtracted again Pressure vacuumizes, and, then with hydrogen purge three times. with nitrogen purging three times.Reactant stirs to three days in a hydrogen atmosphere, so Filtered afterwards by Celite pad, filtrate is washed with ethyl acetate, is then washed with methanol.Filtrate is concentrated, obtains white foam Shape thing (7R) -7- methyl isophthalic acids-[5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane.

To 21.0 grams of (7R) -7- methyl isophthalic acids-[5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-two Azepan adds 29.3 milliliters of triethylamines and 13.2 grams of 2,5- bis- in the solution in 250 milliliters of DMFs Chloro- 1,3- benzoxazoles, and mixture is heated 2 hours in oil bath in 75 DEG C, after being cooled to room temperature, reaction acetic acid second Ester dilutes, and with saturated sodium bicarbonate aqueous solution, water, salt water washing, is dried with magnesium sulfate, residual after being concentrated via rotary evaporation Excess obtains gum by flash column chromatography (hexane/ethyl acetate).The gum is in 150 milliliters of acetic acid It is stirred overnight in the mixture of ethyl ester and 300 milliliters of hexanes, filtering obtains the chloro- 2- of white solid 5- { (5R) -5- methyl -4- [5- Methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane -1- bases } -1,3- benzoxazoles.

¹H-NMR：(CDCl₃, 400Hz)：1.19 (s, 1.7Hz), 1.26 (s, 1.3Hz), 2.15-2.28 (m, 1H), 2.39- 2.42 (m, 3H), 3.06-3.10 (m, 1.3Hz), 3.14-3.22 (m, 2H), 3.40-3.53 (m, 2H), 3.56-3.92 (m, 2H), 3.95-4.25 (m, 2H), 4.55 (d, J=14.4Hz, 0.7Hz), 6.97-7.16 (m, 3H), 7.27-7.36 (m, 2H), 7.69 (s, 1H), 7.79 (t, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), it is shown as MK-4305.

Embodiment 1

MK-4305 prepared by 1.01 grams of preparation examples 1 is weighed, 50 milliliters of ethanol is added and forms suspension；, will under stirring condition Hydrochloric acid solution (dissolving with hydrochloric acid of 220 milligrams of concentration 37% is in 10 milliliters of water) is added dropwise in MK-4305 alcohol suspension, 50 DEG C stirring 1 hour, 50 DEG C be spin-dried for remove solvent, 40 DEG C be dried in vacuo 10 hours, obtain 1.06 grams of MK-4305 hydrochlorides, yield 97.1%.

HPLC sign displays, MK-4305 and hydrochloric acid are about 1: 1 one-tenth MK-4305 hydrochlorides with mol ratio.

Elementary analysis：56.69%C, 16.74%N, the 4.93%H (reason of MK-4305 and hydrochloric acid using mol ratio as 1: 1 one-tenth salt By value：56.63%C, 17.23%N, 4.89%H).

Embodiment 2

MK-4305 prepared by 1.02 grams of preparation examples 1 is weighed, adds 1200 milliliters of EtOH Sonicate dissolvings；, will under stirring condition Hydrochloric acid solution (dissolving with hydrochloric acid of 335 milligrams of concentration 37% is in 15 milliliters of ethanol) is added dropwise in MK-4305 ethanol solution, 30 DEG C stirring 12 hours, 30 DEG C be spin-dried for remove solvent, 25 DEG C be dried in vacuo 15 hours, obtain 1.05 grams of MK-4305 hydrochlorides, yield 95.2%.

Elementary analysis：56.50%C, 17.14%N, the 4.99%H (reason of MK-4305 and hydrochloric acid using mol ratio as 1: 1 one-tenth salt By value：56.63%C, 17.23%N, 4.89%H).

Embodiment 3

MK-4305 prepared by 800 milligrams of preparation examples 1 is weighed, 40 milliliters of ethanol is added and forms suspension；Under stirring condition, Hydrochloric acid solution (dissolving with hydrochloric acid of 350 milligrams of concentration 37% is in 16 milliliters of water) is added dropwise in MK-4305 alcohol suspension, 10 DEG C are stirred 24 hours, and 10 DEG C are spin-dried for removing solvent, and 10 DEG C are dried in vacuo 24 hours, obtain 816 milligrams of MK-4305 hydrochlorides, Yield 94.4%.

Elementary analysis：56.27%C, 16.74%N, the 4.97%H (reason of MK-4305 and hydrochloric acid using mol ratio as 1: 1 one-tenth salt By value：56.63%C, 17.23%N, 4.89%H).

The sample and the sample of embodiment 1 of embodiment 2,3 have same or analogous HPLC and elementary analysis result, illustrate real It is identical material to apply example 2,3 samples and the sample of embodiment 1.

Embodiment 4

500 milligrams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of ether is added and forms suspension (in this suspension The dosage of MK-4305 hydrochlorides be at 30 DEG C its 2 times of solubility in ether), this suspension is stirred 12 hours at 30 DEG C, Filtering, filter cake washs with 6 milliliters of ether, 40 DEG C of dryings 10 hours, obtains the crystalline substance of 475 milligrams of MK-4305 hydrochlorides of the invention Type I.

X-ray powder diffraction figure is as shown in Figure 1.Display：The crystal formation I of MK-4305 hydrochlorides.

IR collection of illustrative plates is as shown in Figure 2.

Embodiment 5

750 milligrams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of isopropyl ethers is added and forms suspension (this suspension The dosage of middle MK-4305 hydrochlorides be at 25 DEG C its 3 times of solubility in isopropyl ether), this suspension is stirred 16 at 25 DEG C Hour, filtering, filter cake washs with 10 milliliters of isopropyl ethers, 30 DEG C of dryings 18 hours, obtains 698 milligrams of MK-4305 salt of the invention The crystal formation I of hydrochlorate.

Embodiment 6

1.25 grams of MK-4305 hydrochlorides of the invention are weighed, adding 50 milliliters of methyl tertiary butyl ether(MTBE)s formation suspension, (this is outstanding In supernatant liquid the dosage of MK-4305 hydrochlorides be at 20 DEG C its 5 times of solubility in methyl tertiary butyl ether(MTBE)), this suspension is existed 20 DEG C are stirred 24 hours, and filtering, filter cake washs with 20 milliliters of methyl tertiary butyl ether(MTBE)s, 10 DEG C of dryings 24 hours, obtain 1.12 grams of sheets The crystal formation I of the MK-4305 hydrochlorides of invention.

Embodiment 7

Weigh 2.5 grams of MK-4305 hydrochlorides of the invention, add 50 milliliters of ether and form suspension (MK- in this suspension The dosage of 4305 hydrochlorides be at 10 DEG C its 10 times of solubility in ether), this suspension is stirred 36 hours at 10 DEG C, mistake Filter, filter cake washs with 50 milliliters of ether, 60 DEG C of dryings 48 hours, obtains the crystal formation of 2.17 grams of MK-4305 hydrochlorides of the invention I。

There is same or analogous XRPD collection of illustrative plates and IR to scheme for the sample that embodiment 5~7 is prepared and the sample of embodiment 4 (not shown) is composed, illustrates that the sample of embodiment 5~7 and the sample of embodiment 4 are identical crystal formations.

Embodiment 8

600 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of acetone is added and forms suspension (in this suspension The dosage of MK-4305 hydrochlorides is 2 times of its solubility in acetone at 30 DEG C), this suspension is stirred 12 hours at 30 DEG C, Filtering, filter cake washs with 3 milliliters of acetone, 40 DEG C of dryings 10 hours, obtains the crystalline substance of 570 milligrams of MK-4305 hydrochlorides of the invention Type II.

X-ray powder diffraction figure is as shown in Figure 3.Display：The crystal formation II of MK-4305 hydrochlorides.

IR collection of illustrative plates is as shown in Figure 4.

Embodiment 9

900 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of butanone is added and forms suspension (in this suspension The dosage of MK-4305 hydrochlorides be at 24 DEG C its 3 times of solubility in butanone), this suspension is stirred 16 hours at 24 DEG C, Filtering, filter cake washs with 4 milliliters of butanone, 30 DEG C of dryings 16 hours, obtains the crystalline substance of 846 milligrams of MK-4305 hydrochlorides of the invention Type II.

Embodiment 10

20 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of ethyl acetate is added and forms suspension (this suspension The dosage of middle MK-4305 hydrochlorides be at 18 DEG C its 5 times of solubility in ethyl acetate), by this suspension in 18 DEG C of stirrings 20 hours, filtering, filter cake washed with 6 milliliters of ethyl acetate, 20 DEG C of dryings 20 hours, obtained 18 milligrams of MK-4305 of the invention The crystal formation II of hydrochloride.

Embodiment 11

50 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of isopropyl acetates is added and forms suspension (this suspension In liquid the dosage of MK-4305 hydrochlorides be at 15 DEG C its 6 times of solubility in isopropyl acetate), by this suspension at 15 DEG C Stirring 24 hours, filtering, filter cake washs with 8 milliliters of isopropyl acetates, 10 DEG C of dryings 48 hours, obtain 44 milligrams it is of the invention The crystal formation II of MK-4305 hydrochlorides.

Embodiment 12

100 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of normal heptanes is added and forms suspension (this suspension The dosage of middle MK-4305 hydrochlorides be at 10 DEG C its 10 times of solubility in normal heptane), this suspension is stirred 36 at 10 DEG C Hour, filtering, filter cake washs with 10 milliliters of normal heptanes, 60 DEG C of dryings 24 hours, obtains 82 milligrams of MK-4305 hydrochloric acid of the invention The crystal formation II of salt.

The sample that embodiment 9~12 is prepared and the sample of embodiment 8 have same or analogous XRPD collection of illustrative plates and IR Collection of illustrative plates (not shown), illustrate that the sample of embodiment 9~12 and the sample of embodiment 8 are identical crystal formations.

Embodiment 13

800 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of ethanol is added and forms suspension (in this suspension The dosage of MK-4305 hydrochlorides is 2 times of its solubility in ethanol at 30 DEG C), this suspension is stirred 12 hours at 30 DEG C, Filtering, filter cake washs with 3 milliliters of ethanol, 40 DEG C of dryings 10 hours, obtains the nothing of 752 milligrams of MK-4305 hydrochlorides of the invention Sizing thing.

X-ray powder diffraction figure is as shown in Figure 5.Display：The amorphous article of MK-4305 hydrochlorides.

IR collection of illustrative plates is as shown in Figure 6.

Embodiment 14

Weigh 1.2 grams of MK-4305 hydrochlorides of the invention, add 10 ml methanols and form suspension (MK- in this suspension The dosage of 4305 hydrochlorides is 3 times of its solubility in methyl alcohol at 26 DEG C), this suspension is stirred 14 hours at 26 DEG C, mistake Filter, filter cake washs with 5 ml methanols, 35 DEG C of dryings 14 hours, obtains the unformed of 1.1 grams of MK-4305 hydrochlorides of the invention Thing.

Embodiment 15

Weigh 2 grams of MK-4305 hydrochlorides of the invention, add 10 milliliters of water and form suspension (MK-4305 in this suspension The dosage of hydrochloride be at 20 DEG C its 5 times of solubility in water), this suspension is stirred 24 hours at 20 DEG C, filtering, filter cake With 7 milliliters of water washings, 10 DEG C of dryings 48 hours, the amorphous article of 1.8 grams of MK-4305 hydrochlorides of the invention is obtained.

Embodiment 16

Weigh 4 grams of MK-4305 hydrochlorides of the invention, add 10 milliliters of sec-butyl alcohols and form suspension (MK- in this suspension The dosage of 4305 hydrochlorides be at 10 DEG C its 10 times of solubility in sec-butyl alcohol), this suspension is stirred 36 hours at 10 DEG C, Filtering, filter cake washs with 10 milliliters of sec-butyl alcohols, 60 DEG C of dryings 24 hours, obtains the nothing of 3.4 grams of MK-4305 hydrochlorides of the invention Sizing thing.

The sample that embodiment 14~16 is prepared has same or analogous XRPD collection of illustrative plates and IR with the sample of embodiment 13 Collection of illustrative plates (not shown), the sample and the sample of embodiment 13 for illustrating embodiment 14~16 are identical materials.

Embodiment 17

MK-4305 prepared by 900 milligrams of preparation examples 1 is weighed, 30 ml methanols is added and forms suspension；Under stirring condition, Sulfuric acid solution (sulfuric acid dissolution of 100 milligrams of concentration 98% is in 4 milliliters of water) is added dropwise in MK-4305 methanol suspension, 30 DEG C are stirred 13 hours, and 50 DEG C are spin-dried for removing solvent, and 40 DEG C are dried in vacuo 10 hours, obtain 956 milligrams of MK-4305 sulfate.

HPLC sign displays, MK-4305 and sulfuric acid are about 2: 1 one-tenth MK-4305 sulfate with mol ratio.

IR collection of illustrative plates is as shown in Figure 7.

Embodiment 18

MK-4305 prepared by 1.2 grams of preparation examples 1 is weighed, 100 milliliters of ethanol is added and forms suspension；, will under stirring condition Sulfuric acid solution (sulfuric acid dissolution of 230 milligrams of concentration 98% is in 13 milliliters of ethanol) is added dropwise in MK-4305 alcohol suspension, 10 DEG C are stirred 24 hours, and 30 DEG C are spin-dried for removing solvent, and 25 DEG C are dried in vacuo 15 hours, obtain 1.27 grams of MK-4305 sulfate.

Embodiment 19

MK-4305 prepared by 1.5 grams of preparation examples 1 is weighed, 40 milliliters of n-butanols is added and forms suspension；Under stirring condition, Sulfuric acid solution (sulfuric acid dissolution of 326 milligrams of concentration 98% is in 20 milliliters of water) is added dropwise to MK-4305 n-butanol suspension In, 50 DEG C are stirred 1 hour, and 10 DEG C are spin-dried for removing solvent, and 10 DEG C are dried in vacuo 24 hours, obtain 1.58 grams of MK-4305 sulfate.

The sample and the sample of embodiment 17 of embodiment 18,19 have same or analogous HPLC analyze datas and IR collection of illustrative plates (not shown), illustrate that embodiment 18,19 samples and the sample of embodiment 17 are identical materials.

Embodiment 20

MK-4305 prepared by 620 milligrams of preparation examples 1 is weighed, 50 milliliters of ethanol is added and forms suspension；Under stirring condition, Phosphoric acid solution (phosphoric acid of 55 milligrams of concentration 85% is dissolved in 10 milliliters of water) is added dropwise in MK-4305 alcohol suspension, 50 DEG C are stirred 1 hour, and 50 DEG C are spin-dried for removing solvent, and 40 DEG C are dried in vacuo 10 hours, obtain 635 milligrams of MK-4305 phosphate.

HPLC sign displays, MK-4305 and phosphoric acid are about 3: 1 one-tenth MK-4305 phosphate with mol ratio.

IR collection of illustrative plates is as shown in Figure 8.

Embodiment 21

MK-4305 prepared by 1.3 grams of preparation examples 1 is weighed, adds 1200 milliliters of isopropanol ultrasonic dissolutions；Under stirring condition, The isopropanol that phosphoric acid solution (phosphoric acid of 160 milligrams of concentration 85% is dissolved in 15 milliliters of isopropanols) is added dropwise to MK-4305 is molten In liquid, 30 DEG C are stirred 12 hours, and 30 DEG C are spin-dried for removing solvent, and 25 DEG C are dried in vacuo 15 hours, obtain 1.34 grams of MK-4305 phosphoric acid Salt.

Embodiment 22

MK-4305 prepared by 1.0 grams of preparation examples 1 is weighed, 40 ml methanols is added and forms suspension；, will under stirring condition Phosphoric acid solution (phosphoric acid of 256 milligrams of concentration 85% is dissolved in 16 milliliters of water) is added dropwise in MK-4305 methanol suspension, 10 DEG C stirring 24 hours, 10 DEG C be spin-dried for remove solvent, 10 DEG C be dried in vacuo 24 hours, obtain 1.03 grams of MK-4305 phosphate.

The sample and the sample of embodiment 20 of embodiment 21,22 have same or analogous HPLC analyze datas and IR collection of illustrative plates (not shown), illustrate that embodiment 21,22 samples and the sample of embodiment 20 are identical materials.

Embodiment 23

Tablet (the every MK-4305 for containing 10 milligrams) formula is as follows：

The crystal formation I of the MK-4305 hydrochlorides of the present invention：10.8 milligrams

Lactose monohydrate：230.7 milligram

Microcrystalline cellulose：120.1 milligram

Ac-Di-Sol：32.0 milligrams

Cataloid：3.2 milligram

Magnesium stearate：3.2 milligram

Amount to：400.0 milligram

The preparation process of tablet is as follows：

The crystal formation I of MK-4305 hydrochlorides is well mixed with lactose monohydrate using equal increments method, then with crystallite After cellulose, Ac-Di-Sol, cataloid, magnesium stearate are well mixed, tabletting in tablet press machine is placed in, is adjusted Nodal plate weight, produces respective tablets, prepares 1000 altogether.

Embodiment 24

Tablet (the every MK-4305 for containing 15 milligrams) formula is as follows：

The crystal formation I of the MK-4305 hydrochlorides of the present invention：16.2 milligrams

Lactose monohydrate：225.3 milligram

Microcrystalline cellulose：120.1 milligram

Ac-Di-Sol：32.0 milligrams

Cataloid：3.2 milligram

Magnesium stearate：3.2 milligram

Amount to：400.0 milligram

The preparation process of the tablet is identical with the preparation process of the tablet of embodiment 23.

Embodiment 25

Tablet (the every MK-4305 for containing 20 milligrams) formula is as follows：

The crystal formation I of the MK-4305 hydrochlorides of the present invention：21.6 milligrams

Lactose monohydrate：219.9 milligram

Microcrystalline cellulose：120.1 milligram

Ac-Di-Sol：32.0 milligrams

Cataloid：3.2 milligram

Magnesium stearate：3.2 milligram

Amount to：400.0 milligram

Embodiment 26-30

The nothing for preparing crystal formation II, MK-4305 hydrochloride with the MK-4305 hydrochlorides of the present invention, MK-4305 hydrochlorides is determined The tablet of type thing, MK-4305 sulfate or MK-4305 phosphate as active constituents of medicine, specification are every 400 milligrams of weight, Contain 10 milligrams, 15 milligrams, 20 milligrams of MK-4305 respectively.

The formula of each tablet is as follows：With reference to the formula of embodiment 23~25, by the MK-4305 hydrochloric acid in embodiment 23~25 The crystal formation I of salt replaces with the MK-4305 hydrochlorides of the present invention, crystal formation II, MK-4305 hydrochloride of MK-4305 hydrochlorides respectively Amorphous article, MK-4305 sulfate or MK-4305 phosphate, in the other components and embodiment 23~25 in each formula It is identical.

The preparation process of each tablet is identical with the preparation process of the tablet of embodiment 23.

Embodiment 31

Capsule (every MK-4305 for containing 10 milligrams) formula is as follows：

Pregelatinized starch：236.2 milligram

Lactose：150.0 milligram

Magnesium stearate：3.0 milligram

Amount to：400.0 milligram

The preparation process of capsule is as follows：

Dry method system is placed in after the crystal formation I of MK-4305 hydrochlorides is well mixed with pregelatinized starch, lactose, magnesium stearate Pelletized in grain machine, obtained dry particl is inputted in capsule filling machine and pours into capsule, corresponding capsule is produced, prepares 1000 altogether Grain.

Embodiment 32

Capsule (every MK-4305 for containing 15 milligrams) formula is as follows：

Pregelatinized starch：230.8 milligram

Lactose：150.0 milligram

Magnesium stearate：3.0 milligram

Amount to：400.0 milligram

The preparation process of the capsule is identical with the preparation process of the capsule of embodiment 31.

Embodiment 33

Capsule (every MK-4305 for containing 20 milligrams) formula is as follows：

Pregelatinized starch：225.4 milligram

Lactose：150.0 milligram

Magnesium stearate：3.0 milligram

Amount to：400.0 milligram

Embodiment 34-38

The nothing for preparing crystal formation II, MK-4305 hydrochloride with the MK-4305 hydrochlorides of the present invention, MK-4305 hydrochlorides is determined The capsule of type thing, MK-4305 sulfate or MK-4305 phosphate as active constituents of medicine, specification are every milli of weight 400 Gram, respectively containing 10 milligrams, 15 milligrams, 20 milligrams of MK-4305.

The formula of each capsule is as follows：With reference to the formula of embodiment 31~33, by the MK-4305 salt in embodiment 31~33 The crystal formation I of hydrochlorate replaces with the MK-4305 hydrochlorides of the present invention, crystal formation II, MK-4305 hydrochloric acid of MK-4305 hydrochlorides respectively Amorphous article, MK-4305 sulfate or the MK-4305 phosphate of salt, respectively in the other components and embodiment 31~33 in formula It is identical.

The preparation process of each capsule is identical with the preparation process of the capsule of embodiment 31.

Embodiment 39

The crystal formation II of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 hydrochlorides to the present invention, The MK-4305 that amorphous article, MK-4305 sulfate, the MK-4305 phosphate of MK-4305 hydrochlorides are prepared with preparation example 1 dissociates Alkali carries out solubility comparison.

The solubility compares combines HPLC detection methods using neopelex solubilising, and concrete operations are：25℃ Under, 10 milligrams of above-mentioned samples and 100 milligrams of neopelexes are taken respectively, are placed in 100 milliliters of vials, add 60 millis Deionized water is risen, 40Khz ultrasound works power ultrasonic 60 minutes, is sampled, filtering, filtrate is placed in 5 milliliters of volumetric flasks, removes water Afterwards, with acetonitrile constant volume, HPLC detectable concentrations.It the results are shown in Table 2.

The solubility testing result of table 2

Sample	Solubility (mcg/ml)
		MK-4305	16.26
The MK-4305 hydrochlorides of the present invention	95.85
		The crystal formation I of the MK-4305 hydrochlorides of the present invention	95.82
The crystal formation II of the MK-4305 hydrochlorides of the present invention	96.13
		The amorphous article of the MK-4305 hydrochlorides of the present invention	103.21
The MK-4305 sulfate of the present invention	102.36
		The MK-4305 phosphate of the present invention	101.27

It can be seen that by the result of table 2, under conditions of adding neopelex in 25 DEG C, water, with MK-4305 ratios Compared with, MK-4305 hydrochlorides of the invention, crystal formation II, MK-4305 salt of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides Amorphous article, MK-4305 sulfate, the MK-4305 phosphate of hydrochlorate all have molten in more preferable solubilizing effect and Geng Gao water Xie Du.Therefore, the crystal formation of crystal formation I or the MK-4305 hydrochloride of MK-4305 hydrochlorides or MK-4305 hydrochlorides containing the present invention The amorphous article or MK-4305 sulfate or the phosphatic solid pharmaceutical preparations of MK-4305 of II or MK-4305 hydrochlorides can have higher Dissolution rate and more preferable bioavilability.

Embodiment 40

Take MK-4305, MK-4305 hydrochlorides, the MK-4305 hydrochlorides of the present invention of the present invention prepared by preparation example 1 Crystal formation I, the present invention MK-4305 hydrochlorides crystal formation II, the present invention MK-4305 hydrochlorides amorphous article, the present invention The MK-4305 phosphate of MK-4305 sulfate and the present invention, tabletting is carried out according to the formula and preparation method of embodiment 23, so The comparison of Dissolution of Tablet is carried out afterwards.

With reference to《Chinese Pharmacopoeia》The leaching condition of " Benorilate Tablets " carries out dissolution determination in 2010 editions, using paddle method, with 900ml 1% lauryl sodium sulfate (SDS) aqueous solution is 50 revs/min as dissolution medium, 37 DEG C of temperature, rotating speed of agitator Clock, 3ml was sampled when 2 minutes, 10 minutes, 20 minutes, 40 minutes, 60 minutes, with 1% dodecyl sulphur after every sub-sampling Sour sodium (SDS) aqueous solution is supplied, and HPLC determines the concentration of each time point sample, calculates accumulative dissolution percentage.It the results are shown in Table 3.

The dissolution data of table 3 compare

It can be seen that by the result of table 3, compared with MK-4305 tablet, MK-4305 hydrochlorides of the invention, MK-4305 hydrochloric acid Amorphous article, MK-4305 sulfate, the MK-4305 of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of salt Phosphatic tablet all has higher dissolution rate and faster dissolution rate, thus can have more preferable bioavilability.

All patent documents quoted in this specification, quoting to be incorporated into a manner of its full text herein.

The above-mentioned general description of invention to being related in the present invention and the description to its embodiment should not be understood For be to the inventive technique scheme form limitation.Those skilled in the art can not disobey according to disclosure of the invention On the premise of the involved invention inscape of the back of the body, to above-mentioned general description or/and embodiment (including embodiment) In public technology feature increased, reduced or combined, formed and belong to other technical schemes of the invention.The present invention's Protection domain should be determined by the scope of protection defined in the claims.

Claims

1. the crystal formation I of structural formula MK-4305 hydrochlorides as follows,

Characterized in that, radiated using Cu-K α, the X-ray powder diffraction figure of the crystal formation I the θ of the angle of diffraction 2 be 6.6 ± 0.2°、9.4±0.2°、11.0±0.2°、12.8±0.2°、14.1±0.2°、16.0±0.2°、17.9±0.2°、18.8± There is characteristic peak at 0.2 °, 20.0 ± 0.2 °, 22.2 ± 0.2 °, 25.0 ± 0.2 ° and 26.0 ± 0.2 °.

2. the crystal formation I of MK-4305 hydrochlorides according to claim 1, it is characterised in that the X- of the MK-4305 crystal formations I is penetrated Line powder diagram is that following opening position has characteristic peak and its relative intensity in the θ of the angle of diffraction 2：

3. the crystal formation I of MK-4305 hydrochlorides according to any one of claim 1~2, it is characterised in that the crystal formation I's FTIR spectrum wave number be 1700,1632,1508,1454,1414,1349,1304,1268,1179,1082,1055, 951st, 884,814 and 704cm^-1Place has characteristic peak.

4. a kind of crystal formation I of MK-4305 hydrochlorides any one of claims 1 to 3 preparation method, including following step Suddenly：By MK-4305 hydrochlorides in C₄~C₆Suspension is formed in ether, stirring and crystallizing, by the crystal separation of precipitation, dries, obtains institute State the crystal formation I of MK-4305 hydrochlorides；The preparation method of the MK-4305 hydrochlorides, comprises the following steps：Selected from water, alcohol or It is 1 by mol ratio in the solvent of its mixture:1~1:2 MK-4305 and mixed in hydrochloric acid simultaneously react, and are removed after the completion of reaction molten Agent, obtain the MK-4305 hydrochlorides.

5. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that the C₄~C₆Ether Selected from ether, isopropyl ether, methyl tertiary butyl ether(MTBE) or its mixture.

6. MK-4305 hydrochloride Forms I according to claim 5 preparation method, it is characterised in that the C₄~C₆Ether For ether.

7. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that the crystal formation I's The operation temperature of preparation method is room temperature.

8. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that in the suspension The dosage of MK-4305 hydrochlorides be operation temperature under its in C₄~C₆2~10 times of solubility in ether.

9. MK-4305 hydrochloride Forms I according to claim 8 preparation method, it is characterised in that in the suspension The dosage of MK-4305 hydrochlorides be operation temperature under its in C₄~C₆2~5 times of solubility in ether.

10. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that the crystallization Time is 12~36 hours.

11. MK-4305 hydrochloride Forms I according to claim 10 preparation method, it is characterised in that the crystallization Time is 12~24 hours.

12. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that the drying Temperature is 10~60 DEG C.

13. MK-4305 hydrochloride Forms I according to claim 12 preparation method, it is characterised in that the drying Temperature is 10~40 DEG C.

14. MK-4305 hydrochloride Forms I according to claim 4 preparation method, it is characterised in that the drying Time is 10~48 hours.

15. MK-4305 hydrochloride Forms I according to claim 14 preparation method, it is characterised in that the drying Time is 10~24 hours.

16. the crystal formation II of structural formula MK-4305 hydrochlorides as follows,

Characterized in that, being radiated using Cu-K α, the MK-4305 crystal formations II has X-ray powder substantially as shown in Figure 3 Diffraction pattern.

17. the crystal formation II of MK-4305 hydrochlorides according to claim 16, it is characterised in that the MK-4305 crystal formations II's FTIR spectrum wave number be 1695,1631,1468,1414,1371,1260,1215,1158,1057,952,924, 878th, 810,770 and 695cm^-1Place has characteristic peak.

18. a kind of crystal formation II of MK-4305 hydrochlorides any one of claim 16~17 preparation method, it include with Lower step：MK-4305 hydrochlorides are formed into suspension in organic solvent, wherein the organic solvent is selected from C₄~C₅Ester, C₃~ C₄Ketone, normal heptane or its mixture, stirring and crystallizing, by the crystal separation of precipitation, dry, obtain the MK-4305 hydrochlorides Crystal formation II；The preparation method of the MK-4305 hydrochlorides, comprises the following steps：In the solvent selected from water, alcohol or its mixture In, it is 1 by mol ratio:1~1:2 MK-4305 and mixed in hydrochloric acid are simultaneously reacted, and solvent is removed after the completion of reaction, obtains the MK- 4305 hydrochlorides.

19. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that described organic Solvent is selected from acetone, butanone, ethyl acetate, isopropyl acetate or normal heptane.

20. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the suspension In liquid the dosage of MK-4305 hydrochlorides be under operation temperature its 2~10 times of solubility in the organic solvent.

21. MK-4305 hydrochloride Forms II according to claim 20 preparation method, it is characterised in that the suspension In liquid the dosage of MK-4305 hydrochlorides be under operation temperature its in the organic solvent solubility for 2~5 times.

22. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the crystal formation The operation temperature of II preparation method is room temperature.

23. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the crystallization Time be 12~36 hours.

24. MK-4305 hydrochloride Forms II according to claim 23 preparation method, it is characterised in that the crystallization Time be 12~24 hours.

25. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the drying Temperature be 10~60 DEG C.

26. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the drying Temperature be 10~40 DEG C.

27. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the drying Time be 10~48 hours.

28. MK-4305 hydrochloride Forms II according to claim 18 preparation method, it is characterised in that the drying Time be 10~24 hours.

29. the amorphous article of structural formula MK-4305 hydrochlorides as follows,

Characterized in that, the MK-4305 amorphous articles have X-ray powder diffraction figure substantially as shown in Figure 5.

30. the amorphous article of MK-4305 hydrochlorides according to claim 29, it is characterised in that the MK-4305 is unformed The FTIR spectrum of thing wave number be 1698,1627,1505,1450,1413,1350,1279,1172,1109,1055, 961st, 824,778 and 702cm^-1Place has characteristic peak.

31. the preparation method of the amorphous article of MK-4305 hydrochlorides any one of a kind of claim 29~30, it includes Following steps：MK-4305 hydrochlorides are formed into suspension in a solvent and stirred, wherein the solvent is selected from water, C₁~C₄Alcohol or Its mixture, by the solid separation of precipitation, dry, obtain the amorphous article of the MK-4305 hydrochlorides；The MK-4305 salt The preparation method of hydrochlorate, comprises the following steps：It is 1 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1:2 MK-4305 and mixed in hydrochloric acid and react, solvent is removed after the completion of reaction, obtains the MK-4305 hydrochlorides.

32. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described molten Agent is selected from methanol, ethanol or water.

33. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that the nothing The operation temperature of the preparation method of sizing thing is room temperature.

34. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described to stir The time mixed is 12~36 hours.

35. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 34, it is characterised in that described to stir The time mixed is 12~24 hours.

36. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described outstanding In supernatant liquid the dosage of MK-4305 hydrochlorides be under operation temperature its 2~10 times of solubility in the solvent.

37. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described outstanding In supernatant liquid the dosage of MK-4305 hydrochlorides be under operation temperature its 2~5 times of solubility in the solvent.

38. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described dry Dry temperature is 10~60 DEG C.

39. the preparation method of the MK-4305 hydrochloride amorphous articles according to claim 38, it is characterised in that described dry Dry temperature is 10~40 DEG C.

40. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described dry The dry time is 10~48 hours.

41. the preparation method of MK-4305 hydrochlorides amorphous article according to claim 31, it is characterised in that described dry The dry time is 10~24 hours.

42. a kind of pharmaceutical composition, its include treatment and/or prevention effective dose selected from any one of claims 1 to 3 The crystal formation II of MK-4305 hydrochlorides any one of the crystal formation I of MK-4305 hydrochlorides, claim 16~17 or right will Seek the amorphous article of MK-4305 hydrochlorides any one of 29~30, and at least one pharmaceutically acceptable carrier or Auxiliary agent.

43. according to claim 42 described pharmaceutical composition, it is characterised in that described pharmaceutical composition is oral dosage form bag Include tablet, capsule, granule, powder and pill.

44. according to claim 43 described pharmaceutical composition, it is characterised in that described pharmaceutical composition is tablet or capsule.

45. any one of the crystal formation I of MK-4305 hydrochlorides any one of claims 1 to 3, claim 16~17 institute State the crystal formation II of MK-4305 hydrochlorides, the amorphous article or power of MK-4305 hydrochlorides any one of claim 29~30 Profit requires that pharmaceutical composition any one of 42-44 is being prepared for treating and/or preventing the god relevant with orexin receptor Purposes in medicine through property and psychiatric disorders and disease；The wherein described nerve and spirituality relevant with orexin receptor Obstacle and disease are in following groups：It is depressed；Anxiety；Habituation；Obsession；Affective disease；Depressibility neuropathy；The heart The severe obstacle in border；Behavioral disorder；Emotionally disturbed；Sexual dysfunction；Sexual psychology dysfunction, sexual disorder；Schizophrenia；Spirit Entanglement；It is dull-witted；Severe baryencephalia and dyskinesia；Eating disorder, bulimia nervosa, cachexia and obesity；It is additive to ingest Behavior；Carousing defaecation influent pH；Angiocardiopathy；Diabetes；Appetite the sense of taste it is disorderly；Vomiting, nausea；Asthma；Cancer；Pa Golden Sen Shi diseases；Cushing's syndrome disease；Basophilic adenoma；Prolactinoma；Hyperprolactinemia；Pituitary gland knurl adenoma； Hypothalamic disorder；IBD；Motility disturbances of the stomach；Gastric ulcer；Froehlich ' s syndromes；Adenohypophysis disease；Pituitary disease； Adenohypophysis deterioration；Adenohypophysis hyperfunction；Hypothalamic adenasthenia；Kallman ' s syndromes；Idiopathic is high Prolactin blood trouble；The inferior colliculus cerebral disorders of growth hormone deficiency；Idiopathic growth deficiency；Nanism；Gigantism；Acromegalia； Biology and day-night rhythm are disorderly；Related to neurological disorders, neuropathic pain and restless leg syndrome is sleep disordered；The heart Tuberculosis, acute and congestive heart failure；Hypopiesia；Hypertension；Urinary retention；Osteoporosis；Angina pectoris；Myocardial infarction；Lack Courageous and upright or haemorrhagic；Subarachnoid hemorrhage；Ulcer；Allergy；Benign prostatauxe；Chronic renal failure；Nephrosis；Sugar is resistance to Reduced by amount；Antimigraine；Hyperalgia；Pain sensitivity, causalgia and allodynia improve or exaggeration；Acute pain Bitterly；Burn pain；Atypical facial pain；Neuropathic pain；Backache；Complex regional pain syndrome i and II；Arthritis Property pain；Sports injury pain；The pain related to infection；Pain after chemotherapy；Post-stroke pain；Postoperative pain；With it is interior The related symptom of dirty pain；Bladder incontinence；Tolerance to anesthetic or the withdrawal to anesthetic；Sleep-disorder；It is ictal thermophilic Sleep disease；Insomnia；Parasomnia；Jet lag；Nerve degeneration kind obstacle；Grey ball-ponto-nigral is degenerated；Epilepsy.