CN106995441B - Crystal form, preparation method, pharmaceutical composition and the purposes of imidazolone compounds - Google Patents

Abstract

The present invention relates to the crystal form of imidazolone compounds, preparation method, pharmaceutical composition and purposes, belong to medical compounds field of crystals.Crystal form provided by the invention is with good stability, is included in good stability under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation, and good stability is also kept in tableting processes.Crystal form provided by the invention has good body absorption metabolisming property, including blood concentration, Drug-time curve AUC, half-life period etc..Moreover, crystal form solution rate of the invention is improved, be conducive to the application on preparation.

Description

Crystal form, preparation method, pharmaceutical composition and the purposes of imidazolone compounds

Technical field

The present invention relates to the crystal form of the imidazolone compounds with PI3K/mTOR dual restraining activities, preparation method, Pharmaceutical composition and purposes belong to medical compounds field of crystals.

Background technique:

Mammal rapamycin target protein (mTOR) is a kind of atypical serine/Serineprotein kinase, belongs to phosphorus - 3 kinases of acyl inositol (phosphoinositide3-kinase, PI3K) associated kinase family member, be intracellular synthesis and The main signal of the cell functions such as catabolism transmits molecule.MTOR signal path has with nutrition, energy state and growth factor Close relationship.It adjust include autophagy, albumen, lipid, lysosome synthesis and energetic supersession, cytoskeletal organization, Multiple cell processes such as cell survival.Under in mammalian cell periphery, nutritional condition constantly changes, mTOR regulate and control synthesis and The conversion of katabolism, so that cell can grow and survive under different nutritional conditions.Since mTOR is in cell Important function, abnormal or imbalance mTOR signal transmitting can lead to the generation (such as the diseases such as cancer) of human diseases.Therefore MTOR signal path is increasingly becoming an important target spot of design anticancer drug.

The activation of PI3K/Akt/mTOR signal path and kinds of tumors generation are closely related, in glioma, breast cancer, ovum MTOR can speed up the cell cycle in nest cancer, reduce Apoptosis, and promote the migration of tumour cell.The activation of mTOR originates in Growth factor receptors on some cell surfaces by ligand activation, for example, EGF-R ELISA and insulin-like growth because Son -1 and -2 (IGF-1 and -2).The activation of receptor leads to the activation of PI3K kinases, so as to cause swashing for downstream effect Akt albumen It is living.Akt be one can be in the regulatory factor of multi-level upper modulating apoptosis in platelets.Inhibit downstream TSC1/2 compound after Akt phosphorylation Object is activated so as to cause mTOR by Rheb.In the downstream of the signal path of PI3K/Akt and PEN/Akt and Ras/Erk1/2, TSC1/2 compound is that the activation of adjusting mTOR plays critical effect.

Have now found that into the cell there is two different mTOR protein complexes, mTORC1 and mTORC2.Both eggs White matter complex includes the unique protein with mTOR interaction, and respectively by different mechanism regulatings.MTOR inhibits The research and development of agent drug have made substantial progress.Rapamycin is first mTOR inhibitors being found, in kinds cancer model In show preferable cancer resistant effect.Although the forms of rapamycin analogs with more preferable pharmacological characteristics is developed, so And clinically applicable forms of rapamycin analogs is but limited in a few cancer.Akt is one of cancer cell survival Important kinases, and mTORC2 can Direct Phosphorylation Akt, this important mTORC2 that is found to be provides newly in the research of anticancer aspect Thinking, while also promoting while acting on the research and development of the second generation anticancer drug of two target spots of mTORC1 and mTORC2.? Inhibit the activity of two mTOR complexs (mTORC1 and mTORC2) to have in cancer cell simultaneously more to make with more effective anticancer extensively With.

Compound 1, entitled 1- ((1s, 4s) -4- hydroxy-cyclohexyl) -3- methyl -8- (6- (the 1- methyl-1 H- pyrazoles-of chemistry 4- yl) pyridin-3-yl) -1H- imidazo [4,5-c] quinoline -2 (3H) -one, it is protein kinase PI3K/mTOR double inhibitor, With structure shown in following formula:

Compound 1

Compound 1 and its pharmaceutically acceptable salt have been disclosed in WO 2015074516A1, it was reported that its in cell and Good pharmaceutical activity is shown in animal model.For this purpose, exploitation is more stable, be more suitable for preparation and Absorption And Metabolism is preferable The crystal form of compound 1 is of great significance to its clinical application.

Summary of the invention

The present invention provides the officinal salt (such as hydrochloride) of compound 1 or the crystal of its hydrate shown in following formula:

Compound 1.

Compound 1 is named as 1- ((1s, 4s) -4- hydroxy-cyclohexyl) -3- methyl -8- (6- (1- methyl-1 H- pyrazoles - 4- yl) pyridin-3-yl) -1H- imidazo [4,5-c] quinoline -2 (3H) -one.The preparation method of the compound 1 and its hydrochloride It is recorded in such as WO2015074516A1 embodiment 18.The full content of the WO2015074516A1 disclosure is to quote Mode is incorporated herein.

The crystal form I of present invention offer 1 hydrochloride monohydrate of compound, which is characterized in that radiated using Cu-K α, with 2 θ The X-ray powder diffraction characteristic peak that angle (°) indicates may include: 9.028 ± 0.2,11.196 ± 0.2,17.393 ± 0.2, 22.504±0.2。

According to the present invention, the crystal form I is radiated using Cu-K α, the X-ray powder diffraction feature indicated with 2 θ angles (°) Peak may include: 9.028 ± 0.2,11.196 ± 0.2,15.406 ± 0.2,16.380 ± 0.2,17.393 ± 0.2,18.066 ±0.2、18.739±0.2、20.894±0.2、22.504±0.2、22.955±0.2。

Preferably, the crystal form I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak packet indicated with 2 θ angles (°) Include: 9.028 ± 0.2,11.196 ± 0.2,15.406 ± 0.2,16.380 ± 0.2,17.393 ± 0.2,18.066 ± 0.2, 18.739±0.2、20.894±0.2、22.504±0.2、22.955±0.2、26.312±0.2、26.918±0.2、 27.556±0.2、35.168±0.2。

It is highly preferred that the crystal form I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak indicated with 2 θ angles (°) Include: 9.028 ± 0.2,11.196 ± 0.2,12.200 ± 0.2,15.406 ± 0.2,16.380 ± 0.2,16.828 ± 0.2, 17.393±0.2、18.066±0.2、18.739±0.2、20.036±0.2、20.894±0.2、22.504±0.2、 22.955±0.2、24.973±0.2、25.505±0.2、26.312±0.2、26.918±0.2、27.556±0.2、 28.403±0.2、29.176±0.2、31.586±0.2、35.168±0.2。

Preferably, crystal form I has Cu-K α radiation X-ray powder diagram substantially as shown in.

The present invention also provides the preparation method A of the crystal form I of 1 hydrochloride monohydrate of compound, comprising:

1) 1 hydrochloride of compound is soluble in water；

2) sodium chloride is added into the solution of step 1)；

3) cooling down, crystallization filters, and it is dry, obtain crystal form I.

In accordance with the present invention it is preferred that

In step 1), water can be heated before or after 1 hydrochloride of compound is added, so that 1 hydrochloride of compound Dissolution；Wherein, the dosage of water can be 2~80 times of 1 hydrochloride weight of compound, such as 4~70 times, 6~60 times, 8~50 Times or 10~25 times；Such as 70-100 DEG C can be heated water to, such as 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C or 95 DEG C；

In step 2), can keep step 1) solution at a temperature of, be added sodium chloride；As example, institute can control The dosage of sodium chloride is stated so that it accounts for the 0.1~26% of total solution weight, such as 0.5~20%, 0.8~15% or 1~10%, Such as 3~5%；

The sodium chloride can be its suitable form, and sodium chloride solution or solid sodium chloride can be used for example.It is preferred that Ground stirs to dissolve after sodium chloride is added；The sodium chloride solution is preferably sodium-chloride water solution, wherein the weight of sodium chloride Percentage composition can for 10% to saturated concentration, such as 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%, 26%；

In step 3), slow cooling it can be filtered, elution, 15 to 60 DEG C or less (such as 20~50 DEG C) crystallizations under stiring ~35 DEG C (such as 20 DEG C, 25 DEG C, 30 DEG C) vacuum drying, obtain the crystal form I of 1 hydrochloride monohydrate of compound.

The present invention also provides the preparation method B of the crystal form I of 1 hydrochloride monohydrate of compound, comprising:

1) 1 hydrochloride of compound is dissolved in ethanol water；

2) cooling down, crystallization filters, and it is dry, obtain crystal form I.

In accordance with the present invention it is preferred that

In step 1), ethanol water can be heated before or after 1 hydrochloride of compound is added, so that compound 1 hydrochloride salt；Wherein, the dosage of ethanol water can be 5~80 times of 1 hydrochloride weight of compound, such as 10~70 Again, 20~60 times or 30~50 times；Ethanol water can be heated to such as 50-100 DEG C, such as 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C or 95 DEG C；

The mass percent of ethyl alcohol can be such as 30~99%, such as 40~98%, 45~95%, 46 in ethanol water ~85%, 48~80%, 50~75% or 60~70%；

In step 2), slow cooling it can be filtered, 15~35 DEG C to 40 DEG C or less (such as 20~30 DEG C) crystallizations under stiring (such as 25 DEG C of room temperature) vacuum drying, obtains the crystal form I of 1 hydrochloride monohydrate of compound.

The present invention also provides the crystal form II of 1 hydrochloride monohydrate of compound, which is characterized in that it is radiated using Cu-K α, with The X-ray powder diffraction characteristic peak that 2 θ angles (°) indicate may include: 8.934 ± 0.2,11.126 ± 0.2,15.367 ± 0.2、22.437±0.2。

According to the present invention, the crystal form II is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) indicate Sign peak includes: 8.934 ± 0.2,11.126 ± 0.2,12.161 ± 0.2,15.367 ± 0.2,16.289 ± 0.2,17.369 ± 0.2、18.037±0.2、18.667±0.2、20.896±0.2、22.437±0.2、22.928±0.2、24.995±0.2、 26.269±0.2、26.890±0.2、27.574±0.2。

Preferably, the crystal form II is radiated using Cu-K α, the X-ray powder diffraction characteristic peak indicated with 2 θ angles (°) Include: 8.486 ± 0.2,8.934 ± 0.2,11.126 ± 0.2,12.161 ± 0.2,13.317 ± 0.2,15.367 ± 0.2, 16.289±0.2、16.742±0.2、17.369±0.2、18.037±0.2、18.667±0.2、19.966±0.2、 20.896±0.2、22.437±0.2、22.928±0.2、24.995±0.2、25.467±0.2、26.269±0.2、 26.890±0.2、27.213±0.2、27.574±0.2、28.366±0.2、29.075±0.2、35.001±0.2。

Preferably, crystal form II has Cu-K α radiation X-ray powder diagram substantially as shown in Figure 8.

The present invention also provides the preparation methods of the crystal form II of 1 hydrochloride monohydrate of compound, comprising:

1) the saturated solution mixing by 1 hydrochloride of compound in two kinds of different solvents；

2) the mixture solvent flashing for making step 1), obtains crystal form II.

Preparation method according to the present invention, it is preferable that

In step 1), two kinds of saturated solutions can be mixed at 10~35 DEG C, at a temperature of preferably 20~25 DEG C；It is described Solvent is selected from organic solvent, such as selected from one of the following or a variety of: esters solvent (such as ethyl acetate, methyl acetate, formic acid Ethyl ester, methyl formate), ketones solvent (such as acetone, 2- butanone), ether solvent (such as tetrahydrofuran, 1,4- dioxane, methyl Tertbutyl ether, methyl isopropyl ether, methyl ethyl ether, ether), nitrile solvents (such as acetonitrile, propionitrile)；Preferably, described two The ratio between respective total volume of saturated solution is 2:1~1:2, such as 1:1；For example, two kinds of saturated solutions can be mixed in 96 orifice plates It closes；

In step 2), the mixture of step 1) can be placed in slow solvent flashing under atmospheric environment；As example, can lead to It crosses and covers 96 orifice plates with the sealed membrane for pricking hole, be placed in draught cupboard, volatilized naturally under atmospheric environment, obtain crystal form II.

The present invention also provides the crystal form III of 1 hydrochloride of compound, which is characterized in that is radiated using Cu-K α, with 2 θ angles The X-ray powder diffraction characteristic peak that (°) indicates may include: 6.396 ± 0.2,7.115 ± 0.2,8.972 ± 0.2,10.803 ±0.2、11.870±0.2、18.542±0.2、23.071±0.2。

According to the present invention, the crystal form III may include: with the X-ray powder diffraction characteristic peak that 2 θ angles (°) indicate 6.396±0.2、7.115±0.2、8.972±0.2、10.803±0.2、11.147±0.2、11.870±0.2、12.139± 0.2、15.417±0.2、16.297±0.2、16.559±0.2、17.374±0.2、18.074±0.2、18.542±0.2、 19.310±0.2、22.464±0.2、23.071±0.2、24.550±0.2、25.843±0.2、26.903±0.2、 28.737±0.2、29.664±0.2、35.016±0.2。

Preferably, crystal form III has Cu-K α radiation X-ray powder diagram substantially as shown in Figure 10.

The present invention also provides the preparation methods of 1 hydrochloride Form III of compound, comprising:

1) the saturated solution mixing by 1 hydrochloride of compound in two kinds of different solvents；

2) the mixture solvent flashing for making step 1), obtains crystal form III.

Preparation method according to the present invention, it is preferable that

It, can be at 35 DEG C hereinafter, it is preferred that mixing two kinds of saturated solutions at 20~25 DEG C in step 1)；The solvent choosing From organic solvent, such as selected from one of the following or a variety of: alcohols solvent (such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, positive fourth Alcohol), ether solvent (such as tetrahydrofuran, 1,4- dioxane, methyl tertiary butyl ether(MTBE), methyl isopropyl ether, methyl ethyl ether, second Ether)；Preferably, the ratio between respective total volume of described two saturated solutions is 2:1~1:2, such as 1:1；For example, can be full by two kinds It is mixed in 96 orifice plates with solution；

In step 2), the mixture of step 1) can be placed in slow solvent flashing under atmospheric environment；As example, can lead to It crosses and covers 96 orifice plates with the sealed membrane for pricking hole, be placed in draught cupboard, volatilized naturally under atmospheric environment, obtain crystal form III.

The present invention also provides the crystal form IV of 1 hydrochloride of compound, which is characterized in that is radiated using Cu-K α, with 2 θ angles The X-ray powder diffraction characteristic peak that (°) indicates may include: 6.178 ± 0.2,8.996 ± 0.2,11.170 ± 0.2, 15.393±0.2、16.343±0.2、17.349±0.2、18.064±0.2、18.708±0.2、19.479±0.2、 19.994±0.2、20.901±0.2、22.470±0.2、22.935±0.2、24.964±0.2、25.504±0.2、 26.287±0.2、26.920±0.2、27.545±0.2。

According to the present invention, the crystal form IV is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) indicate Sign peak may include: 6.178 ± 0.2,6.614 ± 0.2,7.181 ± 0.2,7.470 ± 0.2,8.996 ± 0.2,11.170 ± 0.2、11.723±0.2、12.183±0.2、13.323±0.2、14.412±0.2、15.393±0.2、16.343±0.2、 16.777±0.2、17.349±0.2、18.064±0.2、18.708±0.2、19.479±0.2、19.994±0.2、 20.901±0.2、22.470±0.2、22.935±0.2、24.964±0.2、25.504±0.2、26.287±0.2、 26.920±0.2、27.545±0.2、28.363±0.2、28.841±0.2、29.152±0.2、31.487±0.2、 33.970±0.2、35.136±0.2。

Preferably, crystal form IV has Cu-K α radiation X-ray powder diagram substantially as shown in figure 11.

The present invention also provides the preparation methods of the crystal form IV of 1 hydrochloride of compound, comprising:

1) the saturated solution mixing by 1 hydrochloride of compound in two kinds of different solvents；

2) the mixture solvent flashing for making step 1), obtains crystal form IV.

Preparation method according to the present invention, it is preferable that

It, can be at 35 DEG C hereinafter, it is preferred that mixing two kinds of saturated solutions at 20~25 DEG C in step 1)；The solvent choosing From organic solvent, such as selected from one of the following or a variety of: aromatic hydrocarbon solvent (such as benzene,toluene,xylene, chlorobenzene), esters Solvent (such as ethyl acetate, methyl acetate, Ethyl formate, methyl formate)；Preferably, the respective totality of described two saturated solutions The ratio between product is 2:1~1:2, such as 1:1；For example, two kinds of saturated solutions can be mixed in 96 orifice plates；

In step 2), the mixture of step 1) can be placed in slow solvent flashing under atmospheric environment；As example, can lead to It crosses and covers 96 orifice plates with the sealed membrane for pricking hole, be placed in draught cupboard, volatilized naturally under atmospheric environment, obtain crystal form IV.

The present invention also provides the crystal form V of 1 hydrochloride dihydrate of compound, which is characterized in that is radiated using Cu-K α, with 2 The X-ray powder diffraction characteristic peak that θ angle (°) indicates may include: 6.181 ± 0.2,8.318 ± 0.2,18.223 ± 0.2, 31.778±0.2。

According to the present invention, the crystal form V is radiated using Cu-K α, the X-ray powder diffraction feature indicated with 2 θ angles (°) Peak may include: 6.181 ± 0.2,7.226 ± 0.2,8.318 ± 0.2,9.524 ± 0.2,10.496 ± 0.2,12.037 ± 0.2、18.223±0.2、27.421±0.2、31.778±0.2。

Preferably, crystal form V has substantially Cu-K α radiation X-ray powder diagram as shown in fig. 13 that.

The present invention also provides the preparation methods of the crystal form V of 1 hydrochloride dihydrate of compound, comprising:

1) the salt water saturated solution of 1 hydrochloride of prepare compound；

2) solution of step 1) is placed, crystallization, filters, obtains crystal form V.

Preparation method according to the present invention, it is preferable that

In step 1), the salt water saturated solution of 1 hydrochloride of compound is the sodium chloride water saturation of 1 hydrochloride of compound Solution；In the saturated solution weight percentage of sodium chloride can for 1% to saturated concentration, such as 1%, 5%, 10%, 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%, 26%；

Preferably, the saturated solution of step 1) is from above-mentioned crystal form I preparation method step A 3) filtered mother liquor；

In step 2), the solution can be at 40 DEG C hereinafter, such as 30 DEG C hereinafter, such as 20~25 DEG C of placement 8h or more, example It such as stands overnight, or places more than for 24 hours, such as 36h or more, 48h or more or seven days or more.

The present invention also provides the crystal form VI of 1 hydrochloride dihydrate of compound, which is characterized in that it is radiated using Cu-K α, with The X-ray powder diffraction characteristic peak that 2 θ angles (°) indicate may include: 7.489 ± 0.2,8.897 ± 0.2,11.140 ± 0.2、11.638±0.2、13.348±0.2、13.755±0.2、16.110±0.2、17.152±0.2、18.782±0.2、 19.865±0.2、20.891±0.2、21.477±0.2、25.245±0.2、26.184±0.2、26.431±0.2、 27.242±0.2、28.489±0.2。

According to the present invention, the crystal form VI is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) indicate Levying peak may include: 7.489 ± 0.2,8.153 ± 0.2,8.897 ± 0.2,11.140 ± 0.2,11.638 ± 0.2,13.348 ±0.2、13.755±0.2、14.985±0.2、15.467±0.2、16.110±0.2、17.152±0.2、18.240± 0.2、18.782±0.2、19.865±0.2、20.891±0.2、21.477±0.2、22.333±0.2、22.888±0.2、 25.245±0.2、26.184±0.2、26.431±0.2、27.242±0.2、28.489±0.2、29.710±0.2。

Preferably, crystal form VI has Cu-K α radiation X-ray powder diagram substantially as shown in figure 15.

The present invention also provides the preparation methods of the crystal form VI of 1 hydrochloride dihydrate of compound, comprising:

1) 1 hydrochloride of compound is dissolved in the mixed liquor of water and acetonitrile；

2) it stirs, precipitates crystal, filter, it is dry, obtain crystal form VI.

In accordance with the present invention it is preferred that

It, can be at 40 DEG C hereinafter, such as 30 DEG C hereinafter, be dissolved in water for 1 hydrochloride of compound such as 20~25 DEG C in step 1) In the mixed liquor of acetonitrile；The percent by volume of acetonitrile can be such as 5~99% in the mixed liquor of water and acetonitrile, such as 10~ 95%, 15~75%, 20~60% or 25~50%；

, can be at 40 DEG C hereinafter, such as 30 DEG C such as 20~25 DEG C hereinafter, stir 20 hours in step 2), precipitation is a large amount of white Color crystal filters, and obtained solid is dried in vacuo at 25 DEG C, obtains crystal form VI.

The present invention also provides the crystal form VII of 1 hydrochloride dihydrate of compound, which is characterized in that it is radiated using Cu-K α, With the X-ray powder diffraction characteristic peak that 2 θ angles (°) indicate may include: 6.264 ± 0.2,6.760 ± 0.2,7.556 ± 0.2、14.455±0.2、20.123±0.2、26.373±0.2。

According to the present invention, the crystal form VII is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) indicate Levying peak may include: 6.264 ± 0.2,6.760 ± 0.2,7.556 ± 0.2,11.414 ± 0.2,11.743 ± 0.2,12.488 ±0.2、13.419±0.2、14.455±0.2、17.246±0.2、18.099±0.2、20.123±0.2、21.082± 0.2、25.370±0.2、26.373±0.2、27.294±0.2。

Preferably, crystal form VII has Cu-K α radiation X-ray powder diagram substantially as shown in figure 17.

The present invention also provides the preparation method A of the crystal form VII of 1 hydrochloride dihydrate of compound, comprising:

1) 1 hydrochloride of compound is soluble in water；

2a) by the aqueous solution cooling crystallization of step 1)；Or 2b) sodium chloride, stirring analysis are added into the aqueous solution of step 1) It is brilliant；

3) it filters, it is dry, obtain crystal form VII.

Method in accordance with the invention it is preferred that

In step 1), the dosage of water is 10~500 times of 1 hydrochloride weight of compound, such as 20~200 times, such as 60 or 180 times；Preferably, water is heated before or after 1 hydrochloride of compound is added；It preferably, further include that heat filtering removes not The step of molten object；Such as 70-100 DEG C can be heated water to, such as 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C or 95 DEG C；

Step 2a) in, by the aqueous solution of step 1) be cooled to 40 DEG C hereinafter, such as 30 DEG C hereinafter, such as 20~25 DEG C of crystallizations；

Step 2b) in, at 40 DEG C hereinafter, such as 30 DEG C hereinafter, such as 20~25 DEG C of stirring and crystallizings；Sodium chloride can close for it Sodium chloride solution or solid sodium chloride can be used for example in suitable form.Preferably, it is stirred to dissolve after sodium chloride being added； For example, the dosage of sodium chloride can be 1~15 times of 1 hydrochloride of compound, such as 4~8 times；

Wherein step 2a) and 2b) be to select a progress；

In step 3), the filtering can be to filter, and the drying can be vacuum drying.

The present invention also provides the preparation method B of the crystal form VII of 1 hydrochloride dihydrate of compound, comprising:

By one of above-mentioned crystal form I-VI or a variety of, mixed is carried out using water and is beaten 3 days, crystal form VII is obtained.

Preferably, mixed is beaten at 40 DEG C hereinafter, such as 30 DEG C at 20~25 DEG C hereinafter, as carried out in the method；It is mixed The dosage of water is 20~200 times of crystal form I-VI total weight in rotation mashing, such as 100 times.

The present invention also provides a kind of pharmaceutical compositions, include one of above-mentioned crystal or crystal form or a variety of.

According to the present invention, described pharmaceutical composition also may include pharmaceutically acceptable carrier.

The preferably such carrier of pharmaceutically acceptable carrier, with the consistent concentration of the effective active of active constituent Under to patient's relative nontoxic and harmless so that any side effect as caused by the carrier will not destroy the active constituent Beneficial effect.The pharmacy effective dose of compound or its pharmaceutically acceptable salt preferably generates the specific patient's condition being treated Or the amount that has an impact as a result.Any effective conventional agent including quick-release, sustained release and time release formulation can be used Unit form is measured, the compound of the present invention is given as follows together with pharmaceutically acceptable carrier well known in the art Medicine: oral, parenteral, part, nasal cavity, eye, sublingual, rectum, vagina administration etc..

For oral administration, the compound or its pharmaceutically acceptable salt can be configured to solid or liquid preparation, Such as capsule, pill, tablet, containing pastille (troche), pastille (lozenge), melten gel agent (melt), powder, solution, mixed Suspension or emulsion, and can be prepared according to the method known in the art for being used to prepare pharmaceutical composition.Solid unit dosage form It can be capsule, can be common ebonite bladder type or soft-capsule type, be filled including, for example, surfactant, lubricant and inertia Agent (such as lactose, sucrose, calcium phosphate and cornstarch).

It in another embodiment, can be by the compound of the present invention or its pharmaceutically acceptable salt and conventional tablet bases (such as lactose, sucrose and cornstarch) combines tabletted together and with following substance: adhesive (such as Arabic gum, Cornstarch or gelatin), for tablet after adjunctive administration decomposition and dissolution disintegrating agent (such as potato starch, alginic acid, corn Starch and guar gum, gum tragacanth, Arabic gum), the mobility for improving tablet granulation and prevent tablet material and piece The lubricant (such as talcum, stearic acid or magnesium stearate, calcium stearate or zinc stearate) of the surface adhesion of agent mold and formed punch, Dyestuff, colorant, and organoleptic properties for improving tablet and the flavoring agent for making them be easier to be accepted by patients (such as it is thin Lotus oil, wintergreen or cherry essence).Suitable excipient for oral liquid dosage forms includes Dicalcium Phosphate and diluent, example Such as water and alcohol (such as ethyl alcohol, benzyl alcohol and polyvinyl alcohol), the diluent addition or not added with pharmaceutically acceptable table Face activating agent, suspending agent or emulsifier.There may be various other substances as coating or for changing the object of dosage unit Reason form.Such as tablet, pill or capsule can be coated with shellac, sugar or both.

Also the compound of the present invention can be subjected to parenteral administration with the injection of the compound, i.e., subcutaneously, intravenously, Intraocularly, intrasynovial, intramuscular or Intraperitoneal medication, the injection is preferably in the acceptable dilution of the physiology containing pharmaceutical carrier In agent, the pharmaceutical carrier can be the mixture of sterile liquid or liquid, and the liquid is such as water, salt water, and glucose is water-soluble Liquid and relevant sugar juice, alcohol such as ethyl alcohol, isopropanol or hexadecanol, glycol such as propylene glycol or polyethylene glycol, glycerol ketals Such as 2,2- dimethyl -1,1- dioxolanes -4- methanol, ether such as polyethylene glycol 400 (PEG400), oil, fatty acid, fatty acid Ester or fatty glyceride or acetylated fatty acid glyceride, the diluent add or are not added with pharmaceutically acceptable table Face activating agent, such as soap or detergent, suspending agent such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxylic first Base cellulose or emulsifier and other pharmaceutical auxiliaries.

Exemplary surfactants for parenteral administration are polyethylene sorbitan fatty acid esters, such as de- The high molecular weight adducts of water sorbitol monooleate and ethylene oxide and hydrophobic base, the hydrophobic base by Propylene oxide and propylene glycol are condensed to be formed.

It can will be also administered in the form of the suppository of the rectally of composition of the invention to be used for drug.It can be by by drug It is liquid under rectal temperature and therefore can dissolves in the rectum and discharge the drug with is at normal temperature solid Suitable nonirritant excipient mixes to prepare these compositions.Substance of this kind is such as cocoa butter and polyethylene glycol.

Controlled release preparation for parenteral administration includes liposome microballoon, polymer microballoon and polymer known in the art Gel preparation.

It may need or described pharmaceutical composition must be delivered to patient by mechanical delivery device.For delivering medicament Mechanical delivery device construction and purposes be well known in the art.Such as the direct technology that drug is administered directly to brain is usual It is related to drug delivery tube being placed in the ventricular system of patient around blood-brain barrier.

The compound of the present invention can be administered as single medicament or be administered with one or more other pharmaceutical agent combinations, Described in combination will not cause unacceptable adverse reaction.The invention further relates to such combinations.For example, can be by change of the invention Close object and known chemotherapeutics or anticancer agent (such as anti-hyperproliferative disease or the medicament of other indications etc.) and and it Mixture and combination be combined.Other indication medicaments include but is not limited to anti-angiogenic agent, mitosis inhibition Agent, alkylating agent, antimetabolite, DNA- are embedded in antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topology Isomerase inhibitors, biological response modifier or antihormones.

The present invention also provides one of described crystal form or a variety of, it is used to treat or prevent related to protein kinase activity Disease.

The present invention also provides the method for adjusting (as lower) protein kinase activity, including by the protein kinase with have One of above-mentioned crystal form of effect amount or a variety of contacts.This method can be used in vivo, can be used for external.Preferably, institute It states protein kinase and is selected from least one of mTOR and PI3K.

According to further aspect of the application, this application provides a kind for the treatment of diseases relevant to protein kinase activity Method, the method includes by one of a effective amount of above-mentioned crystal form or a variety of individuals for being applied to this demand.Described Body can be mammal, such as mankind.

Relevant to protein kinase activity disease described in this specification (such as by inhibit it is a kind of in mTOR and PI3K or Two kinds of kinases are come the disease that treats or prevents) it can be tumour, such as leukaemia, malignant lymphoma, Huppert's disease, stomach and intestine Road mesenchymoma, colon and rectum carcinoma, breast cancer, liver cancer, gastric cancer, oophoroma, uterine cancer, cervical carcinoma, carcinoma of vagina, choriocarcinoma, Lung cancer, kidney, prostate cancer, bladder cancer, cancer of pancreas, spongioblastoma, mast cell tumor, brain tumor, reproduction cell are swollen Tumor, melanoma, sarcoma, including dermatofibrosarcoma protuberans, osteosarcoma.It is described herein with protein kinase activity phase The disease of pass can also be metabolic disease (such as diabetes, obesity) and cardiovascular disease (such as atherosclerosis).

The present invention also provides one of described crystal form or a variety of drugs for being used to prepare treatment or prevention disease or illness Purposes, the disease or illness can be disease relevant to protein kinase activity or illness, for example including can pass through inhibition One or two kinds of kinases are in mTOR and PI3K come the disease that treats or prevents.

The present invention also provides one of described crystal form or it is a variety of be used to prepare inhibit it is a kind of in mTOR and PI3K kinases or Purposes in two kinds of drug.

The disease include by uncontrolled cell growth, proliferation and/or survival, unsuitable cellullar immunologic response or Disease caused by unsuitable cellular inflammation response, or with the growth of uncontrolled cell, proliferation and/or survival, discomfort When cellullar immunologic response or unsuitable cellular inflammation response disease, particularly, the disease be such as neoplastic hematologic disorder, reality Body tumor and/or their transfer, such as leukaemia and myelodysplastic syndrome, malignant lymphoma including brain tumor and brain metastes Head and tumor colli, the breast tumor including non-fire power and small cell lung tumor, gastrointestinal tract inside is swollen Tumor, endocrine tumors, tumor of breast and other gynecological tumors, the urinary system including kidney neoplasms, bladder tumor and prostate tumor System tumour, skin neoplasin and sarcoma, and/or their transfer.

The present invention also provides the compound of the present invention and combinations thereof in the hyper-proliferative venereal disease for preparing treatment mammal Purposes in the drug of disease.Can be inhibited using compound, block, reduce, reducing etc. cell Proliferations and/or cell division and/ Or cause apoptosis.Hyperproliferative disorders include but is not limited to psoriasis, keloid and other cutaneous hyperplasia, benign Hyperplasia of prostate (BpH), solid tumor such as breast cancer, respiratory cancer, lung cancer, the cancer of the brain, genital cancer, digestive system cancer, uropoiesis Road cancer, cancer eye, liver cancer, cutaneum carcinoma, head and neck cancer, thyroid cancer, parathyroid carcinoma and their far-end transfer.The illness is also Including lymthoma, sarcoma and leukaemia.

Disease caused by " metabolic disease " used herein refers to because of metabolic problems, including dysbolism and be metabolized it is vigorous Etc. reasons, mainly include these following diseases: diabetes, diabetic ketoacidosis, hyperglycemia hyperosmolality syndrome, hypoglycemia Disease, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis Deng.

" cardiovascular disease " used herein is also known as circulation system disease, be it is a series of be related to the disease of the circulatory system, The circulatory system refers to hemophoric organ and tissue in human body, mainly includes heart, blood vessel (artery, vein, capilary), can be with Be subdivided into it is acute and chronic, it is typically related with artery sclerosis.Cardiovascular disease include: heart disease, low blood pressure, hypertension, Hyperglycemia, apoplexy, myocardial infarction, thrombus, artery sclerosis etc..

These illnesss obtain good characterization in the mankind, but it is dynamic to be also present in other lactations with similar teiology In object, and it can be treated by the way that pharmaceutical composition of the invention is administered.

In some embodiments, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release system Agent, solution and suspension, for the sterile solution, suspension or lotion of parental injection, for the ointment or emulsifiable paste of external application, or Person is used for the suppository of rectally.In other embodiments, described pharmaceutical composition is that single is suitble to bestow exact dose Unit dosage forms.In other embodiments, the amount of the compound is in about 0.001mg/kg body weight/day-about 1000mg/kg body In the range of weight/day.In other embodiments, the range of the amount of the compound be about 0.5mg/kg body weight/day-about 50mg/kg body weight/day.In some embodiments, the amount of the compound is about 0.001g/ days-about 7g/ days.In other realities It applies in mode, the amount of the compound is about 0.002g/ days-about 6g/ days.In other embodiments, the amount of the compound It is about 0.005g/ days-about 5g/ days.In other embodiments, the amount of the compound is about 0.01g/ days-about 5g/ days.? In other embodiment, the amount of the compound is about 0.02g/ days-about 5g/ days.In other embodiments, the compound Amount be about 0.05g/ days-about 2.5g/ days.In other embodiments, the amount of the compound is about 0.1g/ days-about 1g/ It.It in other embodiments, may be enough lower than the dosage level of above range lower limit.In other embodiment In, it may be necessary to higher than the dosage level of the above range upper limit.In some embodiments, the chemical combination is applied with single dose Object, once a day.In other embodiments, the compound is applied with multi-dose, daily more than once.In some embodiment party In formula, the compound twice is applied daily.In other embodiments, the compound three times is applied daily.In other realities It applies in mode, applies four compounds daily.In other embodiments, the chemical combination more than four times is applied daily Object.In some embodiments, the individual that described pharmaceutical composition is applied to is mammal.In other embodiments, institute Stating mammal is people.In other embodiments, described pharmaceutical composition also includes that (one kind is made at least one therapeutic agent Dosage form).In some embodiments, described pharmaceutical composition and at least one therapeutic agent respectively with independent dosage form combination in groups Product is closed, such as covers containing medicines (kitofpart).

Crystal form provided by the invention is with good stability, is included in three kinds of extreme items such as high temperature, high humidity and intense light irradiation It is with good stability under part, and good stability is also kept in tableting processes.Crystal form provided by the invention has Good body absorption metabolisming property, including blood concentration, Drug-time curve AUC, half-life period etc..Moreover, crystal form of the invention is molten Solution speed is improved, and the application on preparation is conducive to.

Technical term of pharmacology

Certain technical term of pharmacology related term " subject ", " patient " or " individual " used herein refers to disease, disease The individual of disease or the patient's condition etc., including mammal and nonmammalian.The embodiment of mammal includes but is not limited to that lactation is dynamic Any member of object guiding principle: people, inhuman primate (such as chimpanzee and other apes and monkey)；Domestic animal, for example, ox, horse, Sheep, goat, pig；Domestic animal, such as rabbit, dog and cat；Laboratory animal, including rodent, for example, rat, mouse and Cavy etc..The embodiment of non-human mammal includes but is not limited to birds and fish etc..In a method provided herein In the embodiment of composition, the mammal is behaved.

The term as used herein " treatment " includes alleviating, mitigate or improving disease or illness disease with other similar synonyms Shape prevents other symptoms, improves or prevents the potential metabolism reason for leading to symptom, inhibit disease or illness, such as prevent disease Or the development of illness, alleviate disease or illness, disease or illness is made to improve, alleviates the symptom as caused by disease or illness, or Stop the symptom of disease or illness, in addition, the term includes the purpose of prevention.The term further include obtain therapeutic effect and/or Preventive effect.The therapeutic effect refers to the potential disease that healing or improvement are treated.In addition, to relevant to potential disease one The healing or improvement of kind or a variety of physiological signs are also therapeutic effect, such as although patient may nevertheless suffer from the shadow of potential disease It rings, but observes that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk Close object, even if not yet make medical diagnosis on disease, but apply institute to the patient for one or more physiological signs of the disease occur State composition.

Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein, which refers to, takes metapedes at certain Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result It can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling " effective quantity " treated is the composition needed for clinically providing significant remission effect comprising compound is disclosed herein Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.

Terms used herein " taking ", " application ", " administration " etc. are to refer to for compound or composition to be delivered to progress The method in the required site of biological effect.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Art technology It can be used for the application technique of Compounds and methods for described herein known to personnel, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon and Remington's, It is discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa Those of.In a preferred embodiment, the compound and composition being discussed herein pass through oral administration.

Refer to herein for term used in preparation, composition or ingredient " acceptable " and docks the one of treated subject As the not long-term adverse effect of health condition.

Detailed description of the invention

Fig. 1 is that crystal form I uses the alpha-emitting X-ray powder diffraction of Cu-K (XRPD) spectrogram in embodiment I-1.

Fig. 2 is thermogravimetic analysis (TGA) (TGA) spectrogram of crystal form I in embodiment I-1.

Fig. 3 is differential scanning calorimetry (DSC) spectrogram of crystal form I in embodiment I-1.

Fig. 4 is the XRPD spectrogram of crystal form I solid under the conditions of 60 DEG C in embodiment I-4.

Fig. 5 is the XRPD spectrogram of crystal form I solid under the conditions of 25 DEG C/90%RH in embodiment I-4.

Fig. 6 is the XRPD spectrogram of crystal form I solid under illumination condition in embodiment I-4.

Fig. 7 is the XRPD comparison diagram in embodiment I-5 before and after crystal form I tabletting.

Fig. 8 is the XRPD spectrogram of crystal form II in embodiment II-1.

Fig. 9 is the TGA spectrogram of crystal form II in embodiment II-1.

Figure 10 is the XRPD spectrogram of crystal form III in embodiment III-1.

Figure 11 is the XRPD spectrogram of crystal form IV in embodiment IV-1.

Figure 12 is the TGA spectrogram of crystal form IV in embodiment IV-1.

Figure 13 is the XRPD spectrogram of crystal form V in embodiment V-1.

Figure 14 is the TGA spectrogram of crystal form V in embodiment V-1.

Figure 15 is the XRPD spectrogram of crystal form VI in embodiment VI-1.

Figure 16 is the TGA spectrogram of crystal form VI in embodiment VI-1.

Figure 17 is the XRPD spectrogram of crystal form VII in embodiment VII-1.

Figure 18 is the TGA spectrogram of crystal form VII in embodiment VII-1.

Figure 19 is differential scanning calorimetry (DSC) spectrogram of crystal form VII in embodiment VII-1.

Specific embodiment

Technical solution of the present invention is described in detail by the following examples, to better understand skill of the invention Art scheme and essence.The exemplary only description of embodiment, is not construed as limiting the scope of the invention.This Field technical staff modification according to made by summary of the invention and following embodiment or change are encompassed by claimed In the range of.

X-ray powder diffraction is measured by Bruker D8advance type X-ray powder diffraction instrument in following embodiment , apparatus preparation LynxEye detector.2 θ scanning angles of sample are from 3 ° to 40 °, and scanning step is 0.02 °, pipe electricity Pressure and tube current are respectively 40KV and 40mA.The sample disc that sample measurement uses is zero Background Samples disk.

Differential scanning calorimetry (DSC) analysis in following embodiment is carried out using TA DSC Q200, corrects the mark used Quasi- sample is indium.2-3mg sample, which is precisely weighed, to be placed in TA DSC sample disc, and records the exact mass of sample.Sample 200-250 DEG C is heated in the nitrogen stream of 50mL/min with the heating rate of 10 DEG C/min.Thermogravimetric point in following embodiment Analysis is carried out using TA TGA Q500.2-3mg sample is placed in Balanced aluminum sample disk, and sample quality is in TGA heating furnace Automatic weighing.Sample is heated to 200-300 DEG C with the rate of 10 DEG C/min.In test process, nitrogen is to balance room and sample room Nitrogen flow be 40mL/min and 60mL/min respectively.

Unless otherwise indicated, the raw material in following examples, substrate or reagent are commercially available commodity (used in such as Dehydrated alcohol is the commercially available pure dehydrated alcohol of analysis), it can also be prepared by methods known in the art.

Embodiment I-1 crystal form I preparation

1 hydrochloride 96g of compound is dissolved in 100 DEG C of bath temperature of 860ml water, 43g solid sodium chloride, stirring are added while hot Under make it dissolve, slow cooling to 30 DEG C of crystallizations, filter simultaneously with 100ml water elute, obtained solid 25 DEG C vacuum drying, obtain The crystallization of 86g yellow green, is after tested the crystal form I of 1 hydrochloride monohydrate of compound.

Embodiment I-2 crystal form I preparation

The hydrochloride 110g of compound 1 is dissolved in 100 DEG C of bath temperature of 2L water, 100g sodium chloride is added while hot in 500ml Solution in water stirs lower slow cooling to 20 DEG C of crystallizations, filters and simultaneously eluted with 100ml water, solid done in 30 DEG C of vacuum It is dry, the crystallization of 97g yellow green is obtained, is after tested the crystal form I of 1 hydrochloride monohydrate of compound.

Embodiment I-3 crystal form I preparation

The hydrochloride 0.5g of compound 1 is dissolved in 85 DEG C of bath temperature of 10ml ethyl alcohol and the mixed liquor of 5.5ml water, under stirring Naturally cool to 25 DEG C of crystallizations, filter, institute solid 25 DEG C be dried in vacuo, obtain 0.36g yellow green crystallization, after tested be change Close the crystal form I of 1 hydrochloride monohydrate of object.

Embodiment I-4 crystal form I stability experiment

The crystal form I for taking 1 hydrochloride monohydrate of compound in a small amount of embodiment I-1 is respectively put into stability of drug products experiment In case, condition listed by control table 1 carries out stability experiment, and purity and content acquired results are listed in Table I -1, crystal form test knot Fruit is as shown in Fig. 4 to 6.

As shown in Table I -1, under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation, the compound purity of crystal form I and contain Amount has no significant change (purity is floated within 0.2%, and content is floated within 1%), it was demonstrated that the stability of crystal form I compared with It is good.

As shown in Figures 4 to 6, under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation, crystal form I keeps crystal form not Become, it was demonstrated that the stability of crystal form I is preferable.

- 1 crystal form I stability experimental result of Table I

Embodiment I-5 crystal form I tabletting stability experiment

The crystal form I for taking 1 hydrochloride monohydrate of compound in a small amount of embodiment 1 is pressed into the tablet that diameter is 8mm manually, Then tablet is gently pulverized, powder carries out XRPD analysis, and result and the XRPD result before tabletting are compared, if figure Shown in 7, to investigate, tableting processes are no to have an impact crystal form.The XRPD map of powder before and after crystal form I tabletting has been carried out pair Than, the results showed that, tableting processes are to crystal form I without change, and the XRPD map of powder is identical before and after tabletting.

Metabolism is administered in the SD Oral Administration in Rats of embodiment I-6 crystal form I

By the sodium carboxymethylcellulose for being suspended in 5.274mL 0.5% of 1 hydrochloride of compound of 11.392mg crystal form I In, it is vortexed, forms uniform suspension, ultrasound 2min is finally made concentration (administration is worked as the uniform suspension solution of 2mg/mL later Its matching while using, storage are no more than 4 hours).To three SD rats press 10mg/kg body weight dose gastric infusion, by setting when Between point take haemanalysis, acquired results are listed in the table below I-2:

Table I -2: crystal form I rat oral gavage drug metabolism experimental data

From Table I -2 it is known that after the drug administration of crystal form I, the reachable 14600ng/ml of highest blood concentration (Cmax), AUC last is up to 190696h*ng/mL, this is very high numerical value in drug metabolism, while the half-life period of 5.5h is also medicine More satisfactory numerical value in object metabolism, it is well-behaved that these all demonstrate the Absorption And Metabolism of the drug of crystal form I in animal body.

Embodiment II-1 crystal form II preparation

At room temperature, by each 100 microlitres of the ethyl acetate saturated solution of 1 hydrochloride of compound and 2- butanone saturated solution, in Mixing in 96 orifice plates is covered with the sealed membrane for pricking hole, is placed in draught cupboard, volatilizes naturally under atmospheric environment, obtain crystal, passed through Test is the crystal form II of 1 hydrochloride monohydrate of compound.

Embodiment II-2 crystal form II preparation

At room temperature, by each 100 microlitres of the tetrahydrofuran saturated solution of 1 hydrochloride of compound and acetonitrile saturated solution, in 96 Mixing in orifice plate is covered with the sealed membrane for pricking hole, is placed in draught cupboard, volatilizes naturally under atmospheric environment, obtain crystal, through surveying Examination is the crystal form II of 1 hydrochloride monohydrate of compound.

Embodiment II-3 crystal form II preparation

At room temperature, by each 100 microlitres of the tetrahydrofuran saturated solution of 1 hydrochloride of compound and acetone saturated solution, in 96 Mixing in orifice plate is covered with the sealed membrane for pricking hole, is placed in draught cupboard, volatilizes naturally under atmospheric environment, obtain crystal, through surveying Examination is the crystal form II of 1 hydrochloride monohydrate of compound.

Embodiment III-1 crystal form III preparation

At room temperature, by each 100 microlitres of the alcohol saturated solution of 1 hydrochloride of compound and isopropanol saturated solution, in 96 holes Mixing in plate is covered with the sealed membrane for pricking hole, is placed in draught cupboard, volatilizes naturally under atmospheric environment, obtain crystal, after tested For the crystal form III of 1 hydrochloride of compound.

Embodiment III-2 crystal form III preparation

At room temperature, the isopropanol saturated solution of 1 hydrochloride of compound and methyl tertiary butyl ether(MTBE) saturated solution each 100 is micro- It rises, is mixed in 96 orifice plates, covered with the sealed membrane for pricking hole, be placed in draught cupboard, volatilized naturally under atmospheric environment, obtain crystalline substance Body is after tested the crystal form III of 1 hydrochloride of compound.

Embodiment IV-1 crystal form IV preparation

At room temperature, by each 100 microlitres of the toluene saturated solution of 1 hydrochloride of compound and isobutyl acetate saturated solution, in Mixing in 96 orifice plates is covered with the sealed membrane for pricking hole, is placed in draught cupboard, volatilizes naturally under atmospheric environment, obtain crystal, passed through Test is the crystal form IV of 1 hydrochloride of compound.

Embodiment V-1 crystal form V preparation

The mother liquor of example I-1 is placed 48 hours for a long time at 20~25 DEG C or more, white crystals are precipitated, filters, obtains Crystal is after tested the crystal form V of 1 hydrochloride dihydrate of compound.

Embodiment V-2 crystal form V preparation

The mother liquor of example I-2 is placed for a long time at 20~25 DEG C, white crystals are precipitated, filters, obtains crystal, after tested For the crystal form V of 1 hydrochloride dihydrate of compound.

Embodiment VI-1 crystal form VI preparation

In the mixed liquor that the hydrochloride 0.5g of compound 1 is dissolved in 50ml water and 20ml acetonitrile in 20~25 DEG C, room temperature is stirred It mixes 20 hours, a large amount of white crystals is precipitated, filter, obtained solid is dried in vacuo at 25 DEG C, 0.27g white crystals is obtained, through surveying Examination is the crystal form VI of 1 hydrochloride dihydrate of compound.

Embodiment VII-1 crystal form VII preparation

The hydrochloride 0.5g of compound 1 is dissolved in and is heated to 90 DEG C of 90ml water, is cooled to room temperature (20~25 DEG C), is stirred Lower addition 3g sodium chloride, is stirred at room temperature 20 hours, and a large amount of white-yellowish solids are precipitated, and filters, and obtained solid is dried in vacuo at 25 DEG C, 0.46g white crystals are obtained, are after tested the crystal form VII of 1 hydrochloride dihydrate of compound.

Embodiment VII-2 crystal form VII preparation

The hydrochloride 0.5g of compound 1 is mainly dissolved in and is heated to 100 DEG C of 12ml water, heat filtering is removed a small amount of insoluble Object is naturally cooled to room temperature (20~25 DEG C) under mother liquor stirring, is filtered, and obtained solid is dried in vacuo at 25 DEG C, and it is white to obtain 0.21g Color crystallization, is after tested the crystal form VII of 1 hydrochloride dihydrate of compound.

Embodiment VII-3 crystal form VII preparation

By above-mentioned crystal form I, 10mg is taken, 1ml water is added, 20~25 DEG C of mixed are beaten 3 days, obtain white crystals, after tested For the crystal form VII of 1 hydrochloride dihydrate of compound.

Embodiment VII-4 crystal form VII preparation

One of above-mentioned crystal form II, III, IV, V, VI are replaced with according to embodiment VII-3, but by crystal form I, is obtained Crystal form VII.

The solution rate of embodiment VII-5 crystal form VII is tested

Taking crystal form VII, crystal form I, each 3mg of crystal form VI are weighed respectively, are respectively put into the plastic centrifuge tube of 3 1ml, often Pipe plus 1ml distilled water are placed after shaking 5 seconds in 20~25 DEG C, observe dissolution phenomena:

Crystal form VII whole dissolved clarifications in 10 seconds；

Crystal form I basic dissolved clarification in 2 hours, whole dissolved clarifications in 5 hours；

Crystal form VI non-dissolved clarification after 5h.

It can be seen that crystal form VII is instant crystal form, there is good application value in terms of making Expidet.

Claims (9)

1. the hydrochloride monohydrate crystal form I of compound 1 shown in following formula, which is characterized in that radiated using Cu-K α, with 2 θ angles The X-ray powder diffraction characteristic peak that (°) indicates includes: 9.028 ± 0.2,11.196 ± 0.2,12.200 ± 0.2,15.406 ± 0.2、16.380±0.2、16.828±0.2、17.393±0.2、18.066±0.2、18.739±0.2、20.036±0.2、 20.894±0.2、22.504±0.2、22.955±0.2、24.973±0.2、25.505±0.2、26.312±0.2、 26.918±0.2,27.556±0.2,28.403±0.2,29.176±0.2,31.586±0.2,35.168±0.2；

2. crystal form I described in claim 1, which is characterized in that crystal form I has Cu-K α radiation X-ray powder as shown in Figure 1 Diffraction pattern.

3. the preparation method of crystal form I as claimed in claim 1 or 2, selected from one of following preparation method A or preparation method B:

Preparation method A, comprising:

1) 1 hydrochloride of compound is soluble in water, 85-100 is heated water to before or after 1 hydrochloride of compound is added DEG C, so that 1 hydrochloride salt of compound；Wherein, the dosage of water is 10~25 times of 1 hydrochloride weight of compound；

2) keep step 1) solution at a temperature of, be added sodium chloride into the solution of step 1), being added after sodium chloride to stir makes It is dissolved；The sodium chloride is sodium-chloride water solution or solid sodium chloride, controls the dosage of the sodium chloride so that it accounts for solution The 3~5% of total weight, when the sodium chloride solution is sodium-chloride water solution, wherein the weight percentage of sodium chloride is 10% to saturated concentration；

3) slow cooling filters, elution, 15~35 DEG C of vacuum drying obtain 1 salt of compound to 20~50 DEG C of crystallizations under stiring The crystal form I of hydrochloride-hydrate；

Alternatively,

Preparation method B, comprising:

1) 1 hydrochloride of compound is dissolved in ethanol water；Wherein, by second before or after 1 hydrochloride of compound is added Alcohol solution is heated to 50-100 DEG C, so that 1 hydrochloride salt of compound；The dosage of ethanol water is 1 hydrochloride of compound 30~50 times of weight；The mass percent of ethyl alcohol is 60~75% in ethanol water；

2) slow cooling filters, 15~35 DEG C of vacuum drying obtain 1 hydrochloride of compound to 20~30 DEG C of crystallizations under stiring The crystal form I of monohydrate.

4. the preparation method of the crystal form V of the hydrochloride dihydrate of compound 1, wherein the compound 1 has in claim 1 Chemical structure, the crystal form V has substantially Cu-K α radiation X-ray powder diagram as shown in fig. 13 that, the preparation Method includes:

1) the salt water saturated solution of 1 hydrochloride of prepare compound, wherein the saturated solution is from system as claimed in claim 3 Preparation Method step A 3) filtered mother liquor；

2) by the solution of step 1) in 20~25 DEG C of 48h or more arranged below, crystallization filters, obtains crystal form V.

5. the preparation method of the crystal form VII of the hydrochloride dihydrate of compound 1, wherein the compound 1 has claim 1 In chemical structure, crystal form VII have Cu-K α radiation X-ray powder diagram substantially as shown in figure 17, the preparation Method includes:

By crystal form I of any of claims 1 or 2, it is beaten 3 days using water in 20~25 DEG C of progress mixed, obtains crystal form VII；It is brilliant Type I is 10mg, water 1mL.

6. pharmaceutical composition includes crystal form I of any of claims 1 or 2.

7. crystal form I of any of claims 1 or 2 is used to prepare the purposes for treating or preventing the drug of disease, the drug is suppression One or two kinds of drug in mTOR and PI3K kinases processed.

8. crystal form I of any of claims 1 or 2 is used to prepare the purposes for treating or preventing the drug of disease or illness, the disease Disease or illness are disease relevant to protein kinase activity or illness.

9. purposes according to any one of claims 8, wherein the drug is controlled by one or two kinds of kinases in inhibition mTOR and PI3K Treat or prevent the disease.