WO2015180060A1 - Salt of diazacycloheptane compound and crystal form and amorphous substance thereof - Google Patents

Abstract

Disclosed are a salt of diazacycloheptane compound and a crystal form and an amorphous substance thereof, which have improved features in the aspects of solubility, stability, dissolution of solid preparations and the like. Also disclosed are methods for preparing the salt and the crystal form and amorphous substance thereof, a pharmaceutical composition thereof and uses of preparing medicaments for treating and preventing neurological and psychiatric disorders and diseases relevant to hypocretin receptors.

Description

 Salt of diazepane compound and crystal form and amorphous form thereof

 The invention relates to the field of medicinal chemical crystallization technology. Specifically, it relates to a diazepane compound

The salt of MK-4305, its crystal form and amorphous form, also relates to the preparation of the salt, its crystal form and amorphous form, its pharmaceutical composition and its use as an orexin receptor antagonist. Background technique

 MK-4305 (English name: Suvorexant) is a new type of hypocretins receptor antagonist developed by Merck Pharmaceuticals to treat or prevent neurological and psychiatric disorders and diseases associated with orexin receptors. Especially as a medicine for treating insomnia sleep disorders. MK-4305 is designed to promote sleep by blocking the neurotransmitters in the brain that help to stay awake. Phase III clinical trial data showed that the drug was used to treat insomnia compared with placebo and was effective in improving sleep maintenance and sleep in patients with insomnia. The dosage form of the MK-4305 clinical trial is tablets, doses of 10 mg to 80 mg.

MK-4305 is a diazepane compound with the chemical name 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2Η-1,2, 3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl1,3-benzoxazole, having the formula C ₂₃ H ₂₃ C1N ₆ 0 ₂ ; 450.9 ; The chemical structural formula is as follows:

 The patent document WO 2008/069997 A1 discloses MK-4305 and its preparation method and use.

The patent document WO 2012/148553 A1 discloses an amorphous type I, an amorphous type II of MK-4305 and a preparation method thereof, and discloses an X-ray diffraction pattern (XRD), a differential scanning analysis chart (DSC) and a ¹³ C-solid state. Characterization data of nuclear magnetic resonance spectroscopy ( ¹³ C-NMR). These two crystal-free types are interconverted with an interconversion temperature of 35 to 40 ° C. At 35 ° C, no crystal type I is the thermodynamically most stable crystal form. At 40 ° C, no crystal type II is the most thermodynamically stable. Crystal form.

The present inventors have found that the above-mentioned amorphous and non-crystalline type II of MK-4305 are both hydrophobic and have extremely poor solubility in water, and are not suitable for use in pharmaceutical dosage forms having high intrinsic solubility requirements. In addition, the intermetallic properties of these two amorphous forms are also a disadvantage that affect formulation development. Therefore, there is still a need in the art to develop new crystalline forms or amorphous forms of MK-4305 or a salt thereof. Summary of the invention

 In view of the deficiencies of the prior art, it is an object of the present invention to provide novel salts of MK-4305, as well as crystalline forms and amorphous forms thereof, as well as processes for their preparation, pharmaceutical compositions and uses.

 Compared with the known MK-4305 and its crystal form, the MK-4305 salt provided by the present invention and its crystal form and amorphous form should have one or more superior properties, for example: good stability including crystal form Stability, thermal stability, chemical stability, mechanical stability, storage stability, etc.; good solubility; fast dissolution rate; high crystallinity; not easy to absorb moisture; easy to purify and handle; high chemical purity; low residual solvent; Good particle morphology; suitable formulation processability such as good fluidity, favorable powder viscosity, tightness and compactability; improved formulation appearance; improved bioavailability and efficacy; extended shelf life; New formulation applications, etc., especially in terms of solubility, dissolution rate, crystal stability, storage stability, etc.

 In accordance with the purpose of the present invention, the present invention provides MK-4305 hydrochloride and its crystalline form and amorphous form, MK-4305 acid salt and MK-4305 phosphate, and processes for their preparation, pharmaceutical compositions and uses.

 The present invention according to the present invention provides MK-4305 hydrochloride having the structural formula shown below:

 HPLC characterization showed that the actual content of MK-4305 free base in MK-4305 hydrochloride was 92.1% and the theoretical content was 92.5%. The test results showed that the MK-4305 hydrochloride was a compound formed by MK-4305 and hydrogen chloride in a molar ratio of about 1:1.

 According to an object of the present invention, the present invention provides a process for the preparation of MK-4305 hydrochloride, the process comprising the steps of: in a solvent selected from the group consisting of water, an alcohol or a mixture thereof, a molar ratio of 1:1 to 1:2 MK-4305 was mixed with hydrochloric acid and reacted, and after completion of the reaction, the solvent was removed to obtain the MK-4305 hydrochloride.

 Preferably, the solvent is selected from the group consisting of water, ethanol or a mixture thereof.

 Preferably, the temperature of the reaction is 10 to 50 ° C, and the reaction time is 1 to 24 hours.

 The "solvent removal" can be accomplished by conventional techniques in the art, such as filtration, centrifugation or spin-drying; preferably, the solvent is removed by spin-drying; the spin-drying process is generally rotary-steamed at a pressure less than atmospheric pressure, preferably. The pressure is less than 0.09 MPa; more preferably, the temperature of the spin-drying method is 10 to 50 °C.

 Preferably, a solution of hydrochloric acid or hydrochloric acid formed in the solvent is added to a solution or suspension of MK-4305 formed in the solvent.

The "hydrochloric acid" is an aqueous solution of hydrogen chloride at a concentration of 37% by weight, which is commercially available. The starting material MK-4305 can be prepared by the method described in Reaction Scheme G of the patent document WO2008069997A1, which is incorporated herein by reference in its entirety. The MK-4305 hydrochloride salt of the invention has the following beneficial properties and application effects:

 1 In the presence of sodium dodecyl sulfate (SDS), the solubility of MK-4305 hydrochloride of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating that MK-4305 hydrochloric acid of the present invention Salt has a better solubilizing effect.

 2 The solid preparation containing the MK-4305 hydrochloride of the present invention has higher dissolution rate and dissolution rate than the solid preparation containing the known MK-4305, and thus has better bioavailability.

 In accordance with the purpose of the present invention, the present invention provides Form 1 of MK-4305 hydrochloride (abbreviated as "Forminium" in the present invention) using Cu-Κα radiation, said Form I is X represented by a diffraction angle of 2Θ The -ray powder diffraction pattern has characteristic peaks at the following positions: 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 preferred embodiment of the invention, Cu-Ka radiation is used, the X-ray powder diffraction pattern of Form I represented by the diffraction angle 2 具有 having a characteristic peak at 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 ^ο , 18.8 ± 0.2 ^ο , 20.0 ± 0.2 ^ο , 22.2 ± 0.2 ^ο , 25.0 ± 0.2 ° and 26.0 ± 0.2 ° .

 In a further preferred embodiment of the invention, Cu-Ka radiation is used, the X-ray powder diffraction pattern of Form I expressed by the diffraction angle 2 具有 having characteristic peaks and their relative intensities at:

 Diffraction angle 2Θ relative intensity%

 6.6 ± 0.2° 31.5

 9.4 ± 0.2° 29.9

 11.0±0.2° 100.0

 12.8 ± 0.2 ° 40.5

 13.3 ± 0.2 ° 11.7

 14.1 ± 0.2° 31.3

 16.0 ± 0.2 ° 42.8

 17.9士 0.2° 30.9

 18.3±0.2° 18.0

 18.8±0.2° 39.5

 20.0 ± 0.2 ° 48.6

 20.9 ± 0.2° 37.0

 22.2 ± 0.2° 59.3

 24.4 ± 0.2° 20.7

 25.0±0.2° 61.0

 26.0 ± 0.2 ° 59.9.

Without limitation, a typical example of the Form I has an X-ray powder diffraction as shown in FIG. 1 and the Fourier infrared spectrum of the Form I is at a wave number of 1700, 1632, 1508, 1454, 1414, 1349, There are characteristic peaks at 1304, 1268, 1179, 1082, 1055, 951, 884, 814 and 704 cm. In accordance with the purpose of the present invention, the present invention provides a process for the preparation of MK-4305 hydrochloride salt form I, which comprises the steps of: forming a suspension of MK-4305 hydrochloride in a C ₄ -C ₆ ether, and agitating the crystal The precipitated crystals were separated and dried to obtain the MK-4305 hydrochloride salt form I.

The C ₄ -C ₆ ether may be diethyl ether, ethyl propyl ether, methyl tert-butyl ether, methyl tert-amyl ether, propyl ether, isopropyl ether; preferably, the C ₄ ~ C ₆ ether It is selected from the group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof; more preferably, the C ₄ -C ₆ ether is diethyl ether.

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

Preferably, the amount of MK-4305 hydrochloride in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the C ₄ -C ₆ ether at the operating temperature.

 Preferably, the crystallization time is from 12 to 36 hours, more preferably from 12 to 24 hours.

 Preferably, the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C.

 Preferably, the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.

 The preparation method of the above crystal form I adopts the crystallization mode of the crystal slurry, and the supersaturated solution of the sample (the presence of insoluble solids) is stirred and crystallized to obtain the desired crystal.

 The MK-4305 hydrochloride salt form I of the present invention has the following beneficial properties and application effects:

 1 In the presence of sodium dodecyl sulfate (SDS), the solubility of MK-4305 hydrochloride salt Form I of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating the MK of the present invention. -4305 hydrochloride salt Form I has a better solubilizing effect.

 2 Compared with the solid preparation containing the known MK-4305, the solid preparation containing the crystalline form I of the MK-4305 hydrochloride of the present invention has higher dissolution rate and dissolution rate, and thus has better bioavailability.

 3 The MK-4305 hydrochloride salt form I of the present invention is placed in a drier at room temperature and a relative humidity of 10% to 90% for 4 months, and its crystal form and melting point are unchanged. It is indicated that the MK-4305 hydrochloride salt form I of the invention has good storage stability, is favorable for adapting to various environmental conditions of manufacture, storage and transportation, and can better resist time in the process of manufacture, storage, transportation, etc. Factors such as uneven content of active substances, decreased purity, and reduced processability of the preparation caused by factors such as humidity, reduce the risk of decline in efficacy and safety risks.

 In accordance with the purpose of the present invention, the present invention provides a crystalline form 11 of MK-4305 hydrochloride (abbreviated as "Form II" in the present invention) using Cu-Κα radiation, said Form II being represented by a diffraction angle of 2Θ The X-ray powder diffraction pattern has characteristic peaks at 16.5 ± 0.2°.

 Without limitation, a typical example of the crystal form II has an X-ray powder diffraction pattern as shown in Fig. 3.

 The Fourier transform infrared spectrum of Form II has characteristic peaks at wavenumbers of 1695, 1631, 1468, 1414, 1371, 1260, 1215, 1158, 1057, 952, 924, 878, 810, 770 and 695 cm.

According to an object of the present invention, the present invention provides a process for the preparation of MK-4305 hydrochloride salt form II, which comprises the steps of: forming a suspension of MK-4305 hydrochloride in an organic solvent, wherein the organic solvent It is selected from the group consisting of c ₄ ~ c ₅ ester, c ₃ ~ c ₄ ketone, n-heptane or a mixture thereof, and the crystal is precipitated by stirring, and the precipitated crystal is separated and dried to obtain the crystal form II.

The c ₄ -c ₅ ester may be ethyl acetate, isopropyl acetate, propyl acetate, ethyl propionate or ethyl isopropylate; the c ₃ -c ₄ ketone may be acetone or butanone.

 Preferably, the organic solvent is selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate or n-heptane. Preferably, the operating temperature of the preparation method is room temperature.

 Preferably, the amount of MK-4305 hydrochloride in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the organic solvent at the operating temperature.

 Preferably, the crystallization time is from 12 to 36 hours, more preferably from 12 to 24 hours.

 Preferably, the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C.

 Preferably, the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.

 The preparation method of the above crystal form II adopts the crystallization mode of the crystal slurry, and the supersaturated solution of the sample (in the presence of insoluble solids) is stirred and crystallized to obtain the desired crystal.

 The MK-4305 hydrochloride salt form II of the invention has the following beneficial properties and application effects:

 1 In the presence of sodium dodecyl sulfate (SDS), the solubility of MK-4305 hydrochloride salt form II of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating the MK of the present invention. -4305 hydrochloride salt form II has a better solubilization effect.

 2 The solid preparation containing the crystalline form II of the present invention MK-4305 hydrochloride has higher dissolution rate and dissolution rate than the solid preparation containing the known MK-4305, and thus has better bioavailability.

 3 The MK-4305 hydrochloride salt form II of the present invention is placed in a desiccator at room temperature and a relative humidity of 10% to 90% RH for 4 months, and its crystal form and melting point are unchanged. It is indicated that the MK-4305 hydrochloride salt form II of the invention has good storage stability, is favorable for adapting to various environmental conditions of manufacture, storage and transportation, and can better resist time in the process of manufacture, storage, transportation, etc. The problems of uneven content of active substances, decreased purity, and reduced processability of the preparation caused by factors such as humidity, etc., reduce the risk of decline in efficacy and safety risks.

 In accordance with the purpose of the present invention, the present invention provides an amorphous form of MK-4305 hydrochloride (referred to in the present invention as "amorphous":).

 Without limitation, a typical example of the amorphous material has an X-ray powder diffraction pattern as shown in Fig. 5.

The Fourier infrared spectrum of the amorphous material has characteristic peaks at wave numbers of 1698, 1627, 1505, 1450, 1413, 1350, 1279, 1172, 1109, 1055, 961, 824, 778, and 702 cm- ¹ .

In accordance with the purpose of the present invention, the present invention provides a process for the preparation of MK-4305 hydrochloride anodate comprising the steps of: forming a suspension of MK-4305 hydrochloride in a solvent and stirring, wherein the solvent is selected from the group consisting of water, d ~ C ₄ alcohols or mixtures thereof, and the precipitated solid was separated, dried, MK-4305 to give the hydrochloride salt was amorphous. The c-C ₄ alcohol may be methanol, ethanol, n-propanol, isopropanol, n-butanol or sec-butanol. Preferably, the solvent is selected from the group consisting of methanol, ethanol or water.

 Preferably, the preparation method has an operating temperature of 10 to 30 °C.

 Preferably, the amount of MK-4305 hydrochloride in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the solvent at the operating temperature.

 Preferably, the time of the mashing is 12 to 36 hours, more preferably 12 to 24 hours.

 Preferably, the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C.

 Preferably, the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.

 The above amorphous form is prepared by a crystallization method of beating, which is a supersaturated solution of the sample.

(There is an insoluble solid present) Stir in a solvent to obtain the desired amorphous material.

 The MK-4305 hydrochloride amorphous form of the invention has the following beneficial properties and application effects:

1 In the presence of sodium dodecyl sulfate (SDS), the solubility of the MK-4305 hydrochloride amorphous form of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating the MK of the present invention. The -4305 hydrochloride amorphous form has a better solubilizing effect.

 2 The solid preparation containing the amorphous substance of MK-4305 hydrochloride of the present invention has higher dissolution rate and dissolution rate than the solid preparation containing the known MK-4305, and thus has better bioavailability.

 3 The MK-4305 hydrochloride amorphous form of the present invention was left in a desiccator at room temperature and a relative humidity of 10% to 90% RH for 4 months, and its XRD pattern was unchanged. It is indicated that the MK-4305 hydrochloride amorphous substance of the invention has good storage stability, is favorable for adapting to various environmental conditions of manufacture, storage and transportation, and can better resist time in the process of manufacture, storage, transportation, etc. Problems such as uneven content of active substances, decreased purity, and reduced processability of the preparation caused by factors such as humidity, reduce the risk of decline in efficacy and safety risks.

 In the preparation method of the crystal form I, the crystal form II and the amorphous form of the MK-4305 hydrochloride of the present invention: "room temperature" means a temperature of 10 to 30 ° C unless otherwise specified.

 The "stirring" can be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to: 1800 rpm, preferably 300 to 900 rpm. The "separation" can be accomplished using conventional techniques in the art, such as filtration, centrifugation, and the like. The filtration is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa. The specific operation of the centrifugation was as follows: The sample to be separated was placed in a 2 ml centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all settled to the bottom of the centrifuge tube.

 Optionally, the crystal form or the amorphous substance obtained after the "separation" is washed, and the solvent used for washing is preferably the same as the solvent used in the preparation method of the crystal form or the amorphous substance, and the amount of the washing solvent is generally a crystal form or The volume of the solvent used in the preparation method of the amorphous material is 0.3 to 1 times.

The "drying" can be accomplished by conventional techniques in the art, such as drying at room temperature, blast drying or reduced pressure drying, and the drying device is a fume hood, a blast oven or a vacuum oven; it can be decompressed or not under reduced pressure. Preferably, the pressure is less than 0.09 MPa.

 In accordance with the purpose of the present invention, the present invention provides a -4305 acid salt having the structural formula shown below

 HPLC characterization showed that the actual content of MK-4305 free base in MK-4305 acid salt was 90.2%, and the theoretical content was 90.0%. The test results showed that the MK-4305 acid salt was a compound formed by MK-4305 and acid in a molar ratio of about 2:1.

The Fourier transform infrared spectrum of the MK-4305 acid salt has characteristics at wave numbers of 1696, 1635, 1621, 1573, 1505, 1451, 1412, 1342, 1263, 1179, 1042, 881, 822, and 786 cm- ¹ . peak.

 According to an object of the present invention, the present invention provides a process for the preparation of MK-4305 acid salt, which comprises the steps of: in a solvent selected from water, an alcohol or a mixture thereof, a molar ratio of 2:1 to 1:1 The MK-4305 was mixed with an acid and reacted, and after the reaction was completed, the solvent was removed to obtain the MK-4305 acid salt.

 Preferably, the solvent is selected from the group consisting of water, methanol, ethanol or a mixture thereof.

 Preferably, the temperature of the reaction is 10 to 50 ° C, and the reaction time is 1 to 24 hours.

 Preferably, the solvent is removed by spin-drying; the spin-drying method is generally carried out by a pressure of less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa; more preferably, the temperature of the spin-drying method is 10 to 50 °C.

 Preferably, a solution of acid or acid in the solvent is added to a solution or suspension of MK-4305 formed in the solvent.

 The "sour acid" is an acidified aqueous solution having a concentration of 98% by weight, which is commercially available.

 The starting material MK-4305 can be prepared by the method described in Reaction Scheme G of WO2008069997A1, which is incorporated herein by reference.

 The MK-4305 acid salt of the invention has the following beneficial properties and application effects:

 1 In the presence of sodium dodecyl sulfate (SDS), the solubility of the MK-4305 acid salt of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating that the MK-4305 of the present invention is sparse The acid salt has a better solubilizing effect.

 2 The solid preparation containing the MK-4305 acid salt of the present invention has higher dissolution rate and dissolution rate than the solid preparation containing the known MK-4305, and thus has better bioavailability.

 In accordance with the purpose of the present invention, the present invention provides MK-4305 phosphate having the structural formula shown below:

HPLC表征显示， MK-4305磷酸盐中 MK-4305游离碱的实际含量为 93.2%， 理论含量为 93.5%。 检测结果表明： 所述 MK-4305磷酸盐是 MK-4305和磷酸以 约 3:1摩尔比形成的化合物。

HPLC characterization showed that the actual content of MK-4305 free base in MK-4305 phosphate was 93.2%, and the theoretical content was 93.5%. The test results showed that the MK-4305 phosphate was a compound formed by MK-4305 and phosphoric acid in a molar ratio of about 3:1.

The Fourier transform infrared spectrum of the MK-4305 phosphate has characteristic peaks at wave numbers of 1,634, 1572, 1506, 1452, 1409, 1375, 1260, 1179, 990, 952, 922, 881, 823, and 726 cm- ¹ .

 In accordance with the purpose of the present invention, the present invention provides a process for the preparation of MK-4305 phosphate, the process comprising the steps of: in a solvent selected from the group consisting of water, an alcohol or a mixture thereof, a molar ratio of from 3:1 to 1:1. MK-4305 and phosphoric acid are mixed and reacted, and after the reaction is completed, the solvent is removed to obtain the MK-4305 phosphate;

 Preferably, the solvent is selected from the group consisting of water, methanol, ethanol or a mixture thereof.

 Preferably, the temperature of the reaction is 10 to 50 ° C, and the reaction time is 1 to 24 hours.

 Preferably, the solvent is removed by spin-drying; the spin-drying method is generally carried out by a pressure of less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa; more preferably, the temperature of the spin-drying method is 10 to 50 °C.

 Preferably, a solution of phosphoric acid or phosphoric acid formed in the solvent is added to a solution or suspension of MK-4305 formed in the solvent.

 The "phosphoric acid" is an aqueous solution of phosphoric acid at a concentration of 85% by weight, which is commercially available.

 The starting material MK-4305 can be prepared by the method described in Reaction Scheme G of WO2008069997A1, which is incorporated herein by reference.

 The MK-4305 phosphate of the invention has the following beneficial properties and application effects:

 1 In the presence of sodium dodecyl sulfate (SDS), the solubility of the MK-4305 phosphate of the present invention in water at 25 ° C is higher than that of the known MK-4305, indicating the MK-4305 phosphate of the present invention. Has a better solubilization effect.

 2 The solid preparation containing the MK-4305 phosphate of the present invention has higher dissolution rate and dissolution rate than the solid preparation containing the known MK-4305, and thus has better bioavailability.

 According to an object of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a crystalline form selected from the group consisting of MK-4305 hydrochloride, MK-4305 hydrochloride of the present invention. Form I, MK-4305 hydrochloride Form II, MK-4305 hydrochloride an amorphous form, MK-4305 acid salt, MK-4305 phosphate or a combination thereof, and at least one pharmaceutically acceptable carrier Or additives. Further, the pharmaceutical composition may further comprise a compound, a crystal form or an amorphous form of another pharmaceutically acceptable MK-4305 or a salt thereof. Optionally, the pharmaceutical composition may further comprise one or more other pharmaceutically acceptable pharmaceutically active ingredients such as sedatives, hypnotics, anxiolytics, antipsychotics, other orexin receptor antagonists and the like.

The pharmaceutical composition may be solid, semi-solid or liquid, prepared as appropriate in a dosage form, by oral, parenteral (eg, muscle, intraperitoneal, intravenous, ICV, intracranial injection or infusion, subcutaneous injection), nasal , vaginal, rectal, sublingual, transdermal, topical, etc. The dosage form may be a solid dosage form such as a tablet, a capsule, a granule, a powder and a pill; a liquid dosage form such as a solution, a syrup, a suspension, a dispersing agent and an emulsion; an injectable preparation such as a solution, a dispersing agent, Suitable for use in liquids prior to injection Lyophilized or dissolved lyophilizate; suppository for rectal administration; topical cream, ointment, gel, solution or suspension; spray for inhalable administration. The formulation may be adapted for rapid release, sustained release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. The pharmaceutical composition is preferably an oral solid dosage form such as a tablet, a capsule, a granule, a powder, a pill or the like, more preferably a tablet and a capsule.

A pharmaceutically acceptable carrier or adjuvant in the pharmaceutical composition, in the case of a solid dosage form, including but not limited to: a carrier, including starch or modified starch, a sugar such as lactose, a cellulose and derivatives thereof such as a powder Cellulose, microcrystalline cellulose, solid inorganic substances such as calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, semi-solids such as lipids or paraffins, mannitol , sorbitol, etc.; binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose , hydroxypropyl methylcellulose, polyethylene glycol, copolyvidone, etc.; disintegrating agents, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, carboxymethyl Cellulose sodium, croscarmellose sodium, colloidal silica, alginic acid, etc.; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, talc, hard Fatty acyl Sodium mareate, polyethylene glycol, etc.; Glidant, such as colloidal silica, light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate; complex forming agents, such as various grades Cyclodextrin and resin; release rate controlling agents such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, methyl methacrylate, wax Wait. Other pharmaceutically acceptable carriers or adjuvants that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. In oral tablets, commonly used carriers include sugars such as lactose, sucrose, mannitol or sorbitol, cellulose products such as corn starch, wheat starch, gelatin, microcrystalline cellulose, hydroxypropyl methylcellulose, methylol Cellulose sodium and polyvinylpyrrolidone, may also be added with a lubricant such as magnesium stearate, a disintegrating agent such as crosslinked polyethylene pyrrolidone, croscarmellose sodium, and further can be packaged in the tablet core Clothes, for example, forming a sugar coating; useful carriers or adjuvants in oral capsules include lactose, high and low molecular weight polyethylene glycols, starch, cellulose derivatives, magnesium stearate, stearic acid and the like; In the case of a soft capsule, the pharmaceutically active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol; in the case of an oral suspension, the pharmaceutically active ingredient is mixed with an emulsifier and a suspending agent. MK-4305 hydrochloride, MK-4305 hydrochloride of the present invention in an oral suspension, if necessary, may be added with a sweetener and/or a flavoring agent and/or a coloring agent. Type I, MK-4305 hydrochloride Form II, amorphous hydrochloride was MK-4305, MK-4305 MK-4305 or a salt repellent phosphate as pharmaceutically active ingredient remains in a solid state form. Each carrier or adjuvant in the pharmaceutical composition must be acceptable, compatible with the other ingredients of the formulation, and not deleterious to the patient. When preparing a pharmaceutical composition, the MK-4305 hydrochloride of the present invention, the crystalline form I of MK-4305 hydrochloride, the crystalline form II of MK-4305 hydrochloride, the amorphous form of MK-4305 hydrochloride, MK -4305 acid salt, MK-4305 phosphate or a combination thereof is admixed with one or more pharmaceutically acceptable carriers or adjuvants, optionally with one or more other pharmaceutically active ingredients. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like. Liquid preparations can be prepared by processes such as dissolution, dispersion, emulsification, and the like.

 According to the object of the present invention, the present invention provides MK-4305 hydrochloride of the present invention, Form I of MK-4305 hydrochloride, Form II of MK-4305 hydrochloride, and amorphous form of MK-4305 hydrochloride. , MK-4305 acid salt, MK-4305 sulphate or the aforementioned crystalline form II or MK-4305 hydrochloride containing the MK-4305 hydrochloride or MK-4305 hydrochloride salt of the invention or A pharmaceutical composition of MK-4305 hydrochloride anhydrate or MK-4305 acid salt or MK-4305 phosphate or a combination thereof for the preparation and/or prevention of neuropathy and spirit associated with orexin receptors Use in drugs for sexual disorders and diseases.

 In accordance with the purpose of the present invention, the present invention provides methods of treating and/or preventing neurological and psychiatric disorders and diseases associated with orexin receptors. In a specific embodiment, the patient is administered the following methods: improving sleep quality; increasing sleep maintenance; increasing REM sleep; increasing sleep 2; reducing sleep rupture; treating insomnia; increasing cognition; increasing memory retention; Obesity; treatment or control of depression; treatment, control, improvement or reduction of the risk of epilepsy, including absence of epilepsy; treatment or control of pain, including neuropathic pain; treatment or control of Parkinson's disease; treatment or control of psychosis; Controlling, ameliorating or reducing the risk of schizophrenia, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a crystalline form I selected from the group consisting of MK-4305 hydrochloride, MK-4305 hydrochloride of the invention Form, M of MK-4305 hydrochloride, amorphous form of MK-4305 hydrochloride, MK-4305 acid salt, MK-4305 sulphate or the aforementioned MK-4305 hydrochloride or MK of the present invention. Form 43 of the hydrochloride salt or Form II of the MK-4305 hydrochloride or the amorphous form of the MK-4305 hydrochloride or the MK-4305 acid salt or the MK-4305 sulphate or a combination thereof combination . Wherein the patient is a mammal including a human. In any event, the pharmaceutically active ingredient administered should contain a sufficient amount of MK-4305 to provide the desired therapeutic effect. The dosage chosen will depend on the desired therapeutic effect, depending on the route of administration and the duration of treatment. The dosage will vary from patient to patient, depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of the drug, and other factors that will be recognized by those skilled in the art. The dosage range will generally be from about 0.5 mg to 1.0 g per day per patient (based on MK-4305 free base), optionally from 0.5 mg to 500 mg, optionally from 0.5 mg to 200 mg, optionally, 5 mg. To 50 mg. It may be administered in a single dose or in multiple doses, and may be administered from 1 to 4 times a day, optionally once or twice daily.

The aforementioned neurological and psychiatric disorders and diseases associated with orexin receptors are selected from the group consisting of: depression; anxiety; addiction; obsessive-compulsive disorder; affective neuropathy; depressive neuropathy; mood disorder; Emotional disorder; sexual dysfunction; sexual dysfunction, sexual disorder; schizophrenia; manic depression; confusion; dementia; severe mental retardation and dyskinesia such as Huntington's disease and Tourette's syndrome; Such as anorexia, excess appetite, cachexia and obesity; addictive feeding behavior; binge drinking @ laxative behavior; cardiovascular disease; diabetes; appetite/taste disorder; vomiting, nausea; asthma; cancer; Parkinson's disease; Syndrome\ disease; basophilic tumor; prolactinoma; hyperprolactinemia; Pituitary tumor / adenoma; hypothalamic disease; inflammatory bowel disease; gastric dyskinesia; gastric ulcer; Froehlich's syndrome; glandular pituitary disease; pituitary gland disease; glandular pituitary function decline; glandular pituitary hyperfunction; Thalamic hypogonadism; Kallman's syndrome (olfactory loss, olfactory loss); idiopathic hyperprolactinemia; hypoglycemic disorder with insufficient growth hormone; idiopathic undergrowth; dwarfism; giant disease; acromegaly; Biology and circadian rhythm disorders; sleep disorders associated with diseases such as neurological disorders, neuropathic pain and restless legs syndrome; cardiopulmonary disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; Osteoporosis; myocardial infarction; ischemic or congestive stroke; subarachnoid hemorrhage; ulcer; allergies; benign prostatic hypertrophy; chronic renal failure; nephropathy; Or exaggerated pain sensitivity such as hyperalgesia, burning neuralgia and allodynia; acute pain; burns Pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; infection-related pain such as HIV; post-chemotherapy pain; post-stroke pain Postoperative pain; neuralgia; vomiting, nausea; symptoms associated with visceral pain such as irritable bowel syndrome, and colic; migraine; bladder incontinence such as urge incontinence; tolerance to anesthetics or withdrawal from anesthetics; Sleep disorders; narcolepsy; insomnia; deep sleep state; jet lag syndrome; and neurodegenerative disorders including disease taxonomy such as inhibition of dementia-Parkinson's disease-muscle atrophy complex; Substantia nigra degeneration; epilepsy; epilepsy and other diseases associated with the general orexin system. DRAWINGS

 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of Form I of MK-4305 hydrochloride salt of the present invention.

 Figure 2 is an IR chart of Form I of MK-4305 hydrochloride of the present invention.

 Figure 3 is an XRPD pattern of Form II of MK-4305 hydrochloride salt of the present invention.

 Figure 4 is an IR chart of Form II of MK-4305 hydrochloride of the present invention.

 Figure 5 is an XRPD pattern of an amorphous form of MK-4305 hydrochloride of the present invention.

 Figure 6 is an IR chart of the amorphous form of the MK-4305 hydrochloride salt of the present invention.

 Figure 7 is an IR chart of the MK-4305 acid salt of the present invention.

 Figure 8 is an IR chart of the MK-4305 phosphate of the present invention. detailed description

 The invention is further described with reference to the following examples which describe in detail the crystalline forms, amorphous forms, and methods of making and their use of the present invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.

 Instruments and methods used to collect data:

X-ray powder diffraction (XPRD): The instrument used was a Bmker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, operating at 40 kV and 40 mA. Under conditions, Θ-2Θ goniometer, Mo monochromator, Lynxeye detector. The instrument is calibrated with silicon carbide before use. The sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate. The detailed test conditions are as follows, angle range: 3- 40 ° 2 Θ, step size: 0.02 ° 2 Θ, speed: 0.2 sec / step.

Infrared spectroscopy (IR) data is taken from BmkerTensor 27, instrument control software and data analysis software are OPUS, usually using ATR equipment, infrared absorption spectrum is collected in the range of όΟΟ ^ΟΟ^η- ¹ , scanning of samples and blank background The time is 16 seconds, the resolution of the instrument is ^! !!— ¹ .

 Nuclear magnetic resonance spectroscopy (^HNMR) data was taken from Bmker Ascend Tm 500. Use full frequency excitation, spectral width 30PPM, single pulse, 30. Angle excitation, scanning 16 times, digital orthogonal detection, temperature control 298K.

 High performance liquid phase analysis (HPLC) data was taken from Waters 2487/2695. Using a C18 column, 150mm x 4.6mm, column temperature 25 ° C, wavelength 254 nm, flow rate 1.0 ml / min, injection volume 80 μl, run time 15 minutes. The solvent was 0.05% aqueous trifluoroacetic acid: acetonitrile = 1:1, mobile phase A was 0.05% aqueous trifluoroacetic acid, and mobile phase B was acetonitrile. The gradient is shown in Table 1.

 HPLC gradient

 Organic element analysis (C, H, N, 0, S) data was collected on CE-400, using horizontal injection combustion, thermal conductivity detector, sample volume: 1~5 mg, analysis time: analysis of C, H, N, Less than 5 minutes, range: lOOppm to 100%.

 The various reagents used in the examples were commercially available unless otherwise specified.

 The temperature in the examples is room temperature unless otherwise specified.

 The "ultrasound" described in the examples can promote the dissolution of the sample by: placing the container containing the sample suspension in an ultrasonic cleaner and sonicating at a power of 20 Khz to 40 Khz for 1 to 60 minutes. Ultrasound is usually performed at 40Khz for 5 minutes unless otherwise specified.

Preparation example 1

The preparation of the MK-4305 free base can be carried out according to the method described in Reaction Scheme G of WO 2008/069997 A1 wherein the compound used can be prepared according to the method described in WO 2008/069997 A1. Specifically: to 22.3 g of (5R)-5-methyl-1,4-diazepane-1-carboxylate hydrochloride, 15.9 g of 2-(2Η-1,2,3-three Zyridin-2-yl)-5-methylbenzoic acid, 12.8 g of 1-hydroxy-7-azacyclobenzotriazole and 43.1 ml of N-methylmorpholine in 300 ml of hydrazine, hydrazine-dimethylformamide 22.5 g of hydrazine-(3-dimethylaminopropyl) was added to the solution, and the reaction was stirred at room temperature overnight, and the reaction was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The mixture was partitioned between EtOAc (EtOAc) elute elute elut elut elut elut elut Benzyl methyl-4-[5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate .

 Will contain 29.6 g of (5R)-5-methyl-4-[5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepine A solution of hexane heterocycloheptane-1-carboxylate in 300 ml of ethyl acetate and 200 ml of methanol was placed in a flask under vacuum, and was purged with nitrogen three times. To the flask was added 2.4 g of 20% palladium hydroxide on carbon. The flask was again vacuumed under reduced pressure and purged with nitrogen three times and then with hydrogen. The reaction was stirred under a hydrogen atmosphere for three days, then filtered through a pad of Celite, and the filtrate was washed with ethyl acetate and then washed with methanol. The filtrate was concentrated to give a white foam (7R)-7-methyl-1-[5-methyl-2-(2?-1,2,3-triazol-2-yl)benzoyl]-1 , 4-diazepane.

 To 21.0 g of (7R)-7-methyl-1-[5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl]-1,4-diaza To a solution of cyclohexane in 250 ml of hydrazine, hydrazine-dimethylformamide, 29.3 ml of triethylamine and 13.2 g of 2,5-dichloro-1,3-benzoxazole were added, and the mixture was placed in an oil bath. After heating at 75 ° C for 2 hours, after cooling to room temperature, the reaction was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, brine, dried over magnesium sulfate, and concentrated by rotary evaporation. Column chromatography (hexane/ethyl acetate) gave a gum. The gum was stirred overnight in a mixture of 150 ml of ethyl acetate and 300 ml of hexanes and filtered to afford 5-chloro-2-{(5R)-5-methyl-4-[5-methyl- 2-(2Η-1,2,3-Triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole.

1.19(s,l .7Hz),l .26(s,l .3Hz),2.15-2.28(m,lH),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,lH),7.7 9(t,J=7.6Hz,lH),7.92(d,J=8.0Hz,lH), 显示为 MK-4305。

1.19(s,l.7Hz), l.26(s,l.3Hz), 2.15-2.28(m,lH), 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 = 14.4 Hz, 0.7 Hz), 6.97-7.16 (m, 3H), 7.27-7.36 (m, 2H), 7.69 (s, lH), 7.7 9 (t, J = 7.6 Hz, lH), 7.92 (d, J = 8.0 Hz, lH), shown as MK -4305.

Example 1

 1.01 g of MK-4305 prepared in Preparation Example 1 was weighed out, and 50 ml of ethanol was added to form a suspension; under stirring, a hydrochloric acid solution (220 mg of 37% hydrochloric acid dissolved in 10 ml of water) was added dropwise to MK-4305. The ethanol suspension was stirred at 50 ° C for 1 hour, dried at 50 ° C to remove the solvent, and vacuum dried at 40 ° C for 10 hours to obtain 1.06 g of MK-4305 hydrochloride, yield 97.1%.

 HPLC characterization showed that MK-4305 and hydrochloric acid were in a molar ratio of about 1:1 to MK-4305 hydrochloride. Elemental analysis: 56.69% C, 16.74% N, 4.93% H (MK-4305 and hydrochloric acid in a molar ratio of 1:1 salt: 56.63% C, 17.23% N, 4.89% H).

Example 2

1.02 g of MK-4305 prepared in Preparation Example 1 was weighed and dissolved in 1200 ml of ethanol; the hydrochloric acid solution (335 mg of 37% hydrochloric acid dissolved in 15 ml of ethanol) was added dropwise to MK-4305 under stirring. The mixture was stirred at 30 ° C for 12 hours in an ethanol solution, and the solvent was removed by spin-drying at 30 ° C, and dried under vacuum at 25 ° C for 15 hours to obtain 1.05 g of MK-4305 hydrochloride, yield 95.2%. HPLC characterization showed that MK-4305 and hydrochloric acid were in a molar ratio of about 1:1 to MK-4305 hydrochloride. Elemental analysis: 56.50% C, 17.14% N, 4.99% H (MK-4305 and hydrochloric acid in a molar ratio of 1:1 salt: 56.63% C, 17.23% N, 4.89% H).

Example 3

 Weigh 800 mg of MK-4305 prepared in Preparation Example 1, and add 40 ml of ethanol to form a suspension. Under stirring, a hydrochloric acid solution (350 mg of 37% hydrochloric acid dissolved in 16 ml of water) was added dropwise to MK-4305. The ethanol suspension was stirred at 10 ° C for 24 hours, and the solvent was removed by spinning at 10 ° C, and dried under vacuum at 10 ° C for 24 hours to obtain 816 mg of MK-4305 hydrochloride, yield 94.4%.

 HPLC characterization showed that MK-4305 and hydrochloric acid were in a molar ratio of about 1:1 to MK-4305 hydrochloride. Elemental analysis: 56.27% C, 16.74% N, 4.97% H (MK-4305 and hydrochloric acid in a molar ratio of 1:1 salt: 56.63% C, 17.23% N, 4.89% H).

 The samples of Examples 2 and 3 have the same or similar HPLC and elemental analysis results as the samples of Example 1, indicating that the samples of Examples 2 and 3 are the same as those of Example 1.

Example 4

 Weigh 500 mg of the MK-4305 hydrochloride of the present invention, and add 50 ml of diethyl ether to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 2 times the solubility in diethyl ether at 30 ° C), The suspension was stirred at 30 ° C for 12 hours, filtered, and the filter cake was washed with 6 ml of diethyl ether and dried at 40 ° C for 10 hours to obtain 475 mg of the crystalline form I of the MK-4305 hydrochloride salt of the present invention.

 The X-ray powder diffraction pattern is shown in Figure 1. Display: Form I of MK-4305 hydrochloride.

 The IR spectrum is shown in Figure 2.

Example 5

 Weigh 750 mg of the MK-4305 hydrochloride of the present invention, and add 50 ml of isopropyl ether to form a suspension (the amount of MK-4305 hydrochloride in this suspension is 3 in its solubility in isopropyl ether at 25 ° C) The suspension was stirred at 25 ° C for 16 hours, filtered, and the filter cake was washed with 10 ml of isopropyl ether and dried at 30 ° C for 18 hours to obtain 698 mg of the crystal form of MK-4305 hydrochloride of the present invention. I.

Example 6

 Weigh 1.25 g of the MK-4305 hydrochloride of the present invention, and add 50 ml of methyl tert-butyl ether to form a suspension (the amount of MK-4305 hydrochloride in this suspension is 20 ° C in methyl tert-butyl The solution was stirred at 20 ° C for 24 hours, filtered, and the filter cake was washed with 20 ml of methyl t-butyl ether and dried at 10 ° C for 24 hours to obtain 1.12 g of the present invention. Form I of MK-4305 hydrochloride.

Example 7

Weigh 2.5 g of the MK-4305 hydrochloride of the present invention, and add 50 ml of diethyl ether to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 10 times of the solubility in diethyl ether at 10 ° C), The suspension was stirred at 10 ° C for 36 hours, filtered, and the filter cake was washed with 50 ml of diethyl ether and dried at 60 ° C for 48 hours to obtain 2.71 g of the crystalline form I of the MK-4305 hydrochloride salt of the present invention. The samples prepared in Examples 5 to 7 had the same or similar XRPD patterns and IR patterns (not shown) as the samples of Example 4, indicating that the samples of Examples 5 to 7 were the same crystal form as the sample of Example 4. . Example 8

 Weigh 600 mg of the MK-4305 hydrochloride of the present invention, and add 10 ml of acetone to form a suspension (the amount of MK-4305 hydrochloride in the suspension is twice the solubility in acetone at 30 ° C), The suspension was stirred at 30 ° C for 12 hours, filtered, and the filter cake was washed with 3 ml of acetone and dried at 40 ° C for 10 hours to obtain 570 mg of the crystalline form II of MK-4305 hydrochloride of the present invention.

 The X-ray powder diffraction pattern is shown in Figure 3. Display: Form II of MK-4305 hydrochloride.

 The IR spectrum is shown in Figure 4.

Example 9

 Weigh 900 mg of the MK-4305 hydrochloride of the present invention, and add 10 ml of methyl ethyl ketone to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 3 times that in the butanone at 24 ° C) The suspension was stirred at 24 ° C for 16 hours, filtered, and the filter cake was washed with 4 ml of methyl ethyl ketone and dried at 30 ° C for 16 hours to obtain 846 mg of the crystal form II of MK-4305 hydrochloride of the present invention.

Example 10

 Weigh 20 mg of the MK-4305 hydrochloride of the present invention, and add 10 ml of ethyl acetate to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 5 in the solubility in ethyl acetate at 18 ° C) The suspension was stirred at 18 ° C for 20 hours, filtered, and the filter cake was washed with 6 ml of ethyl acetate and dried at 20 ° C for 20 hours to obtain 18 mg of the crystal form of MK-4305 hydrochloride of the present invention. II.

Example 11

 Weigh 50 mg of the MK-4305 hydrochloride of the present invention, and add 10 ml of isopropyl acetate to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 15 ° C in its solubility in isopropyl acetate) 6 times), the suspension was stirred at 15 ° C for 24 hours, filtered, and the filter cake was washed with 8 ml of isopropyl acetate and dried at 10 ° C for 48 hours to obtain 44 mg of the MK-4305 hydrochloride of the present invention. Form II.

Example 12

 100 mg of the MK-4305 hydrochloride of the present invention was weighed, and 10 ml of n-heptane was added to form a suspension (the amount of MK-4305 hydrochloride in the suspension was 10 in 10% of the solubility in n-heptane). The suspension was stirred at 10 ° C for 36 hours, filtered, and the filter cake was washed with 10 ml of n-heptane and dried at 60 ° C for 24 hours to obtain 82 mg of the crystal form of MK-4305 hydrochloride of the present invention. II.

 The samples prepared in Examples 9 to 12 had the same or similar XRPD patterns and IR patterns (not shown) as the samples of Example 8, indicating that the samples of Examples 9 to 12 were the same crystal form as the sample of Example 8. . Example 13

Weigh 800 mg of the MK-4305 hydrochloride of the present invention, and add 10 ml of ethanol to form a suspension (the amount of MK-4305 hydrochloride in the suspension is twice the solubility in ethanol at 30 ° C), The suspension was stirred at 30 ° C for 12 hours, filtered, and the filter cake was washed with 3 ml of ethanol and dried at 40 ° C for 10 hours. 752 mg of the amorphous form of MK-4305 hydrochloride of the present invention.

 The X-ray powder diffraction pattern is shown in Figure 5. Display: Amorphous of MK-4305 hydrochloride.

 The IR spectrum is shown in Figure 6.

Example 14

 Weigh 1.2 g of the MK-4305 hydrochloride of the present invention, and add 10 ml of methanol to form a suspension (the amount of MK-4305 hydrochloride in this suspension is 3 times its solubility in methanol at 26 ° C), The suspension was stirred at 26 ° C for 14 hours, filtered, and the filter cake was washed with 5 ml of methanol and dried at 35 ° C for 14 hours to obtain 1.1 g of the amorphous form of MK-4305 hydrochloride of the present invention.

Example 15

 Weigh 2 g of the MK-4305 hydrochloride of the present invention, and add 10 ml of water to form a suspension (the amount of MK-4305 hydrochloride in the suspension is 5 times that in water at 20 ° C), The suspension was stirred at 20 ° C for 24 hours, filtered, and the filter cake was washed with 7 ml of water and dried at 10 ° C for 48 hours to obtain 1.8 g of the amorphous form of MK-4305 hydrochloride of the present invention.

Example 16

 4 g of the MK-4305 hydrochloride of the present invention was weighed, and 10 ml of sec-butanol was added to form a suspension (the amount of MK-4305 hydrochloride in the suspension was 10 in 10% of the solubility in sec-butanol). The suspension was stirred at 10 ° C for 36 hours, filtered, and the filter cake was washed with 10 ml of sec-butanol and dried at 60 ° C for 24 hours to obtain 3.4 g of the amorphous form of MK-4305 hydrochloride of the present invention. Things.

 The samples prepared in Examples 14 to 16 had the same or similar XRPD patterns and IR patterns (not shown) as the samples of Example 13, indicating that the samples of Examples 14 to 16 were the same as the samples of Example 13. Example 17

 Weigh 900 mg of MK-4305 prepared in Preparation Example 1, add 30 ml of methanol to form a suspension; and dilute the acid solution (100 mg of 98% acid in 4 ml of water) to the MK- The methanol suspension of 4305 was stirred at 30 ° C for 13 hours, dried at 50 ° C to remove the solvent, and vacuum dried at 40 ° C for 10 hours to obtain 956 mg of MK-4305.

 HPLC characterization showed that MK-4305 and the acid were in a molar ratio of about 2:1 to MK-4305.

The IR spectrum is shown in Figure 7.

Example 18

 Weigh 1.2 g of MK-4305 prepared in Preparation Example 1, add 100 ml of ethanol to form a suspension; and dilute the acid solution (230 mg of 98% acid in 18 ml of ethanol) to the MK under stirring The -4305 ethanol suspension was stirred at 10 ° C for 24 hours, dried at 30 ° C to remove the solvent, and vacuum dried at 25 ° C for 15 hours to obtain 1.27 g of MK-4305 acid salt.

 HPLC characterization showed that MK-4305 and the acid were in a molar ratio of about 2:1 to MK-4305. Example 19

Weigh 1.5 g of MK-4305 prepared in Preparation Example 1, and add 40 ml of n-butanol to form a suspension; Under hydrazine conditions, add an acid solution (326 mg of 98% acid in 20 ml of water) to the solution.

The n-butanol suspension of MK-4305 was stirred at 50 ° C for 1 hour, and the solvent was removed by spinning at 10 ° C, and dried under vacuum at 10 ° C for 24 hours to obtain 1.58 g of MK-4305.

 HPLC characterization showed that MK-4305 and the acid were in a molar ratio of about 2:1 to MK-4305. Samples of Examples 18, 19 and Examples 17 samples have the same or similar HPLC analytical data and

The IR spectrum (not shown) indicates that the samples of Examples 18 and 19 were the same as the samples of Example 17. Example 20

 Weigh 620 mg of MK-4305 prepared in Preparation Example 1, and add 50 ml of ethanol to form a suspension. Under stirring, a phosphoric acid solution (55 mg of 85% phosphoric acid dissolved in 10 ml of water) was added dropwise to MK-4305. The ethanol suspension was stirred at 50 ° C for 1 hour, dried at 50 ° C to remove the solvent, and vacuum dried at 40 ° C for 10 hours to obtain 635 mg of MK-4305 phosphate.

 HPLC characterization showed that MK-4305 and phosphoric acid were in a molar ratio of about 3:1 to MK-4305 phosphate.

The IR spectrum is shown in Figure 8.

Example 21

 1.3 g of MK-4305 prepared in Preparation Example 1 was weighed, and ultrasonically dissolved in 1200 ml of isopropanol; and a phosphoric acid solution (160 mg of 85% phosphoric acid dissolved in 15 ml of isopropanol) was added dropwise thereto under stirring. The solution of MK-4305 in isopropanol was stirred at 30 ° C for 12 hours, dried at 30 ° C to remove the solvent, and dried under vacuum at 25 ° C for 15 hours to obtain 1.34 g of MK-4305 phosphate.

 HPLC characterization showed that MK-4305 and phosphoric acid were in a molar ratio of about 3:1 to MK-4305 phosphate. Example 22

 1.0 g of MK-4305 prepared in Preparation Example 1 was weighed, and 40 ml of methanol was added to form a suspension; and a phosphoric acid solution (256 mg of 85% phosphoric acid dissolved in 16 ml of water) was added dropwise to MK-4305 under stirring conditions. The methanol suspension was stirred at 10 ° C for 24 hours, dried at 10 ° C to remove the solvent, and vacuum dried at 10 ° C for 24 hours to obtain 1.03 g of MK-4305 phosphate.

 HPLC characterization showed that MK-4305 and phosphoric acid were in a molar ratio of about 3:1 to MK-4305 phosphate. The samples of Examples 21, 22 and the samples of Example 20 had the same or similar HPLC analysis data and IR spectra (not shown), indicating that the samples of Examples 21 and 22 were the same as the samples of Example 20. Example 23

 The tablets (10 mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 10.8 mg

 Lactose monohydrate: 230.7 mg

 Microcrystalline cellulose: 120.1 mg

 Croscone sodium: 32.0 mg

 Colloidal silica: 3.2 mg

Magnesium stearate: 3.2 mg Total: 400.0 mg

 The preparation steps of the tablet are as follows:

 Form I of MK-4305 hydrochloride and lactose monohydrate are mixed in an equal amount, followed by microcrystalline cellulose, croscarmellose sodium, colloidal silica, magnesium stearate After mixing, the tablets were placed in a tableting machine to adjust the tablet weight, and the corresponding tablets were obtained. A total of 1000 tablets were prepared.

Example 24

 The tablets (15 mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 16.2 mg

 Lactose monohydrate: 225.3 mg

 Microcrystalline cellulose: 120.1 mg

 Croscone sodium: 32.0 mg

 Colloidal silica: 3.2 mg

 Magnesium stearate: 3.2 mg

 Total: 400.0 mg

 The preparation procedure of the tablet was the same as that of the tablet of Example 23.

Example 25

 The tablets (20 mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 21.6 mg

 Lactose monohydrate: 219.9 mg

 Microcrystalline cellulose: 120.1 mg

 Croscone sodium: 32.0 mg

 Colloidal silica: 3.2 mg

 Magnesium stearate: 3.2 mg

 Total: 400.0 mg

 The preparation procedure of the tablet was the same as that of the tablet of Example 23.

Example 26-30

 Preparation of MK-4305 hydrochloride of the present invention, Form II of MK-4305 hydrochloride, Amorph of MK-4305 hydrochloride, MK-4305 acid salt or MK-4305 phosphate as a pharmaceutical active ingredient The tablets, weighing 400 mg each, contain 10 mg, 15 mg, and 20 mg of MK-4305, respectively.

 The formulation of each tablet was as follows: With reference to the formulations of Examples 23 to 25, the crystal form I of MK-4305 hydrochloride in Examples 23 to 25 was replaced with MK-4305 hydrochloride, MK-4305, respectively. The crystalline form of the hydrochloride salt, the amorphous form of MK-4305 hydrochloride, the MK-4305 acid salt or the MK-4305 phosphate, the other components in each formulation are the same as in Examples 23-25.

The preparation steps of each tablet were the same as those of the tablet of Example 23. Example 31

 Capsules (10 mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 10.8 mg

 Pregelatinized starch: 236.2 mg

 Lactose: 150.0 mg

 Magnesium stearate: 3.0 mg

 Total: 400.0 mg

 The preparation steps of the capsule are as follows:

 The crystal form I of MK-4305 hydrochloride is mixed with pregelatinized starch, lactose and magnesium stearate, and then placed in a dry granulator to be granulated, and the obtained dry granules are input into a capsule filling machine. Capsules, that is, corresponding capsules, a total of 1000 capsules were prepared.

Example 32

 Capsules (15 mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 16.2 mg

 Pregelatinized starch: 230.8 mg

 Lactose: 150.0 mg

 Magnesium stearate: 3.0 mg

 Total: 400.0 mg

 The preparation procedure of the capsule was the same as that of the preparation of the capsule of Example 31.

Example 33

 Capsules (20mg each containing MK-4305) are formulated as follows:

 Form I of MK-4305 hydrochloride of the present invention I: 21.6 mg

 Pregelatinized starch: 225.4 mg

 Lactose: 150.0 mg

 Magnesium stearate: 3.0 mg

 Total: 400.0 mg

 The preparation procedure of the capsule was the same as that of the preparation of the capsule of Example 31.

Example 34-38

 Preparation of MK-4305 hydrochloride of the present invention, Form II of MK-4305 hydrochloride, Amorph of MK-4305 hydrochloride, MK-4305 acid salt or MK-4305 phosphate as a pharmaceutical active ingredient The capsules are 400 mg each, containing 10 mg, 15 mg, and 20 mg of MK-4305, respectively.

The formulation of each capsule was as follows: According to the formulations of Examples 31 to 33, the crystal form I of MK-4305 hydrochloride in Examples 31 to 33 was replaced with MK-4305 hydrochloride, MK-4305, respectively. The crystalline form of the hydrochloride salt, the amorphous form of the hydrazine-4305 hydrochloride, the MK-4305 acid salt or the MK-4305 phosphate, the other components in each of the formulations were the same as those in Examples 31 to 33. The preparation steps of each capsule were the same as those of the capsule of Example 31.

Example 39

 MK-4305 hydrochloride of the present invention, Form I of MK-4305 hydrochloride, Form II of MK-4305 hydrochloride, Amorph of MK-4305 hydrochloride, MK-4305 acid salt, The solubility of MK-4305 phosphate was compared with the MK-4305 free base prepared in Preparation Example 1.

 The solubility is compared by sodium dodecylbenzene sulfonate solubilization combined with HPLC detection, the specific operation is: at 25 ° C, take 10 mg of the above sample and 100 mg of sodium dodecylbenzene sulfonate, placed at 100 In a milliliter glass vial, add 60 ml of deionized water, 40 Khz ultrasonic working power for 60 minutes, sample, filter, and place the filtrate in a 5 ml volumetric flask. After removing the water, make up to volume with acetonitrile and measure the concentration by HPLC. The results are shown in Table 2.

 Solubility test result

 From the results of Table 2, it can be seen that MK-4305 hydrochloride and MK-4305 hydrochloride of the present invention are compared with MK-4305 under the condition of adding sodium dodecylbenzenesulfonate in water at 25 ° C. Form I, MK-4305 hydrochloride Form II, MK-4305 hydrochloride anion, MK-4305 acid salt, MK-4305 phosphate have better solubilization effect and higher Solubility in water. Therefore, the amorphous form of Form II or MK-4305 hydrochloride containing Form I or MK-4305 hydrochloride of MK-4305 hydrochloride or MK-4305 hydrochloride of the present invention or MK-4305 is sparse. A solid formulation of the acid salt or MK-4305 phosphate can have a higher dissolution rate and better bioavailability. Example 40

 Taking the MK-4305 prepared in Preparation Example 1, the MK-4305 hydrochloride of the present invention, the crystalline form I of the MK-4305 hydrochloride of the present invention, the crystalline form II of the MK-4305 hydrochloride of the present invention, and the present invention The amorphous form of MK-4305 hydrochloride, the MK-4305 acid salt of the present invention and the MK-4305 phosphate of the present invention were tableted according to the formulation and preparation method of Example 23, and then the tablet dissolution rate was carried out. Comparison.

Refer to the Chinese Pharmacopoeia 2010 edition of the "Benoester Tablets" dissolution conditions for dissolution determination, using the paddle method, with 900 ml of 1% sodium dodecanoate (SDS) aqueous solution as the dissolution medium, temperature 37 ° C, Stirring speed of 50 rpm, sampling 3 ml at 2 minutes, 10 minutes, 20 minutes, 40 minutes, 60 minutes, respectively, using 1% sodium dodecanoate (SDS) aqueous solution after each sampling Complement, HPLC determination of each time Point the concentration of the sample and calculate the cumulative percentage of dissolution. The results are shown in Table 3.

 Table 3 Comparison of dissolution data

 As can be seen from the results in Table 3, the indole-4305 hydrochloride of the present invention, the crystalline form I of the indole-4305 hydrochloride, the crystalline form II of the indole-4305 hydrochloride, and the indole compared to the tablet of ΜΚ-4305. The -4305 hydrochloride an amorphous form, the ΜΚ-4305 acid salt, and the ΜΚ-4305 phosphate tablets all have higher dissolution rates and faster dissolution rates, thus providing better bioavailability. All of the patent documents cited in the present specification are hereby incorporated by reference in their entirety. The above general description of the invention and the description of the specific embodiments thereof are not to be construed as limiting the invention. According to the disclosure of the present invention, those skilled in the art can increase or decrease the above-mentioned general description or/and the specific technical features in the specific embodiments (including the embodiments) without departing from the inventive constituent elements involved. Or a combination, forming other technical solutions belonging to the invention. The scope of protection of the present invention should be defined by the scope of the claims

Claims

Rights request 1. MK-4305 hydrochloride as shown below

2. A process for the preparation of MK-4305 hydrochloride according to claim 1, comprising the steps of: MK-4305 having a molar ratio of 1:1 to 1:2 in a solvent selected from the group consisting of water, an alcohol or a mixture thereof Hydrochloric acid is mixed and reacted, and after the reaction is completed, the solvent is removed to obtain the MK-4305 hydrochloride;  Preferably, the solvent is selected from the group consisting of water, ethanol or a mixture thereof;  Preferably, the temperature of the reaction is 10 to 50 ° C, and the reaction time is 1 to 24 hours; preferably, the solvent is removed by spin-drying; more preferably, the temperature of the spin-drying method is 10~ 50 ° C; Preferably, a solution of hydrochloric acid or hydrochloric acid formed in the solvent is added to a solution or suspension of MK-4305 formed in the solvent.  3. A crystalline form I of MK-4305 hydrochloride according to claim 1 wherein the X-ray powder diffraction pattern of said Form I is 6.6 ° ± at a diffraction angle of 2 使用 using Cu-Ka radiation. 0.2, 9.4 ± 0.2 °, 11.0 ± 0.2 °, 12.8 ± 0.2. 14.1 ± 0.2. And 16.0 ± 0.2. There are characteristic peaks. 4. The crystal form of MK-4305 hydrochloride according to claim 3, wherein the X-ray powder diffraction pattern of the ΜΚ-4305 crystal form I is 6.6 ± 0.2°, 9.4 ± 0.2 at a diffraction angle of 2 Θ . , 11.0 ± 0.2. 12.8 ± 0.2. 14.1±0.2 ^ο , 16.0 ± 0.2 ^ο , 17.9 ± 0.2 ^ο , 18.8 ± 0.2 ^ο , 20.0 ± 0.2 ^ο , 22.2 ± 0.2 ^ο , 25.0 ± 0.2 . And characteristic peaks at 26.0 ± 0.2°.  The crystal form of the ΜΚ-4305 hydrochloride according to claim 4, wherein the X-ray powder diffraction pattern of the ΜΚ-4305 crystal form I has a characteristic peak at a diffraction angle of 2 Θ and Relative strength: diffraction angle 2Θ relative intensity%  6.6 ± 0.2° 31.5 7, preparation of Form I of the hydrochloride salt of an MK-4305 in any of claims 3 to 6, comprising the steps of: MK-4305 hydrochloride formed was suspended in C ₄ ~ C ₆ ether The liquid is stirred and crystallized, and the precipitated crystal is separated and dried to obtain the crystal form I of the MK-4305 hydrochloride; Preferably, the C ₄ -C ₆ ether is selected from the group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof; more preferably, the C ₄ -C ₆ ether is diethyl ether;  Preferably, the operating temperature of the preparation method is room temperature; Preferably, the amount of MK-4305 hydrochloride in the suspension is 2 to 10 times, more preferably 2 to 5 times, the solubility in the C ₄ -C ₆ ether at the operating temperature;  Preferably, the crystallization time is 12 to 36 hours, more preferably 12 to 24 hours;  Preferably, the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C;  Preferably, the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.  8. A crystalline form II of MK-4305 hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern of said Form II is at a diffraction angle of 26.5 ± 16.6 using Cu-Ka radiation. There is a characteristic peak at °.  9.4 ± 0.2° 29.9  10. The crystalline form II of MK-4305 hydrochloride according to claim 8 or 9, wherein the Fourier transform infrared spectrum of the MK-4305 crystal form II is at a wave number of 1695, 1631, 1468, 1414, There are characteristic peaks at 1371, 1260, 1215, 1158, 1057, 952, 924, 878, 810, 770 and 695 cm.  11.0±0.2° 100.0  12.8 ± 0.2 ° 40.5  13.3 ± 0.2 ° 11.7  14.1 ± 0.2° 31.3 15. A process for the preparation of an amorphous form of MK-4305 hydrochloride according to any one of claims 12 to 14 which comprises the steps of: forming a suspension of MK-4305 hydrochloride in a solvent and stirring袢, wherein the solvent is selected from the group consisting of water, d-C ₄ alcohol or a mixture thereof, and the precipitated solid is separated and dried to obtain an amorphous substance of the MK-4305 hydrochloride;  Preferably, the solvent is selected from the group consisting of methanol, ethanol or water;  Preferably, the operating temperature of the preparation method is room temperature;  Preferably, the time of the mashing is 12 to 36 hours, more preferably 12 to 24 hours;  Preferably, the amount of MK-4305 hydrochloride in the suspension is 2 to 10 times, more preferably 2 to 5 times, the solubility in the solvent at the operating temperature;  Preferably, the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C;  Preferably, the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.

 16.0 ± 0.2 ° 42.8 17.9 ± 0.2 ° 30.9 18.3±0.2° 18.0  19. Structure MK-4305 phosphate as shown below

 20.0 ± 0.2 ° 48.6  A method for producing a phosphate of MK-4305 according to claim 19 or 20, which comprises the steps of: MK-4305 having a molar ratio of from 3:1 to 1:1 in a solvent selected from the group consisting of water, an alcohol or a mixture thereof Mixing with phosphoric acid and reacting, after the reaction is completed, removing the solvent to obtain the MK-4305 phosphate;  Preferably, the solvent is selected from the group consisting of water, methanol, ethanol or a mixture thereof;  Preferably, the temperature of the reaction is 10 to 50 ° C, and the reaction time is 1 to 24 hours; preferably, the solvent is removed by spin-drying; more preferably, the temperature of the spin-drying method is 10~ 50 ° C; Preferably, a solution of phosphoric acid or phosphoric acid formed in the solvent is added to a solution or suspension of MK-4305 formed in the solvent.  22.2 ± 0.2° 59.3  24.4 ± 0.2° 20.7  25.0±0.2° 61.0  26.0 ± 0.2° 59.9  The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is an oral solid dosage form including a tablet, a capsule, a granule, a powder, and a pill; more preferably, the pharmaceutical composition is a tablet. Agent or capsule. The MK-4305 hydrochloride according to claim 1, the crystal form I of the MK-4305 hydrochloride according to any one of claims 3 to 6, and the MK-4305 according to any one of claims 8 to 10. Form II of the hydrochloride salt, the amorphous form of the MK-4305 hydrochloride salt according to any one of claims 12 to 14 , the MK-4305 acid salt of claim 16 or 17, the claim 19 or 20 Use of the MK-4305 phosphate or the pharmaceutical composition according to claim 22 or 23 for the preparation of a medicament for the treatment and/or prevention of neurological and psychiatric disorders and diseases associated with orexin receptors; Neurological and psychiatric disorders associated with orexin receptors And the disease is selected from the group consisting of: depression; anxiety; addiction; obsessive-compulsive disorder; affective neuropathy; depressive neuropathy; mood disorder; behavioral disorder; mood disorder; sexual dysfunction; sexual psychological dysfunction, sexual disorder Schizophrenia; manic depression; insanity; dementia; severe mental retardation and dyskinesia such as Huntington's disease and Tourette's syndrome; eating disorders such as anorexia, excess appetite, cachexia and obesity; addictive feeding behavior狂饮\ laxative eating behavior; cardiovascular disease; diabetes; appetite/pain disorder; vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome\ disease; basophilic adenoma; Hyperprolactinemia; pituitary tumors/adenomas; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcer; Froehlich's syndrome; glandular pituitary disease; pituitary gland disease; glandular pituitary function decline; Glandular pituitary hyperfunction; hypothalamic hypogonadism; Kallman's syndrome; idiopathic hyperprolactinemia; growth Hormone-deficient hypothalamic disorder; idiopathic undergrowth; dwarfism; giant disease; acromegaly; biological and circadian rhythm disorders; sleep associated with diseases such as neurological disorders, neuropathic pain, and restless legs syndrome Disorder; cardiopulmonary disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or congestive stroke; subarachnoid hemorrhage; ulcer; allergies; Prostatic hypertrophy; Chronic renal failure; Kidney disease; Reduced glucose tolerance; Migraine; Hyperalgesia; Pain; Increased or exaggerated pain sensitivity such as hyperalgesia, burning neuralgia and allodynia; Acute pain; Burn pain; Type of facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; infection-related pain such as HIV; post-chemotherapy pain; post-stroke pain; Pain; neuralgia; vomiting, nausea; symptoms associated with visceral pain such as irritable bowel Syndrome and colic; migraine; bladder incontinence such as urge incontinence; tolerance to anesthetics or withdrawal from anesthesia; sleep disorders; narcolepsy; insomnia; deep sleep state; jet lag syndrome; neurodegenerative disorders include Diseases of disease classification such as inhibition of dementia-Parkinson's disease-muscle atrophy complex; globus-cerebral bridge-substantia nigra degeneration; epilepsy; epilepsy and other diseases associated with the general orexin system.