CN106995441A - Crystal formation, its preparation method, pharmaceutical composition and the purposes of imidazolone compounds - Google Patents
Crystal formation, its preparation method, pharmaceutical composition and the purposes of imidazolone compounds Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to the crystal formation of imidazolone compounds, its preparation method, pharmaceutical composition and purposes, belong to medical compounds field of crystals.The crystal formation that the present invention is provided has good stability, and being included under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation has good stability, and also keeps in tableting processes good stability.The crystal formation that the present invention is provided has good body absorption metabolisming property, including blood concentration, Drug-time curve AUC, half-life period etc..Moreover, the crystal formation dissolution velocity of the present invention is improved, be conducive to the application on preparation.
Description
Technical field
The present invention relates to the crystal formation of the imidazolone compounds with PI3K/mTOR dual restraining activities, its preparation method, medicine
Compositions and purposes, belong to medical compounds field of crystals.
Background technology：
Mammal rapamycin target protein (mTOR) is a kind of atypical serine/Serineprotein kinase, belongs to phosphatidyl
The kinases of inositol -3 (phosphoinositide3-kinase, PI3K) associated kinase family member is intracellular synthesis and is decomposed generation
The main signal transmission molecule of cell function such as thank.MTOR signal paths have closely with nutrition, energy state and growth factor
Relation.It, which is adjusted, includes autophagy, albumen, lipid, lysosome synthesis and energetic supersession, cytoskeletal organization, cell
Multiple cell processes such as survival.In the case where mammalian cell periphery nutritional condition is continually changing, mTOR regulates and controls synthesis and degraded
The conversion of metabolism, so that cell can grow and survive under different nutritional conditions.Due to weights of the mTOR in cell
Act on, abnormal or imbalance mTOR signals transmission can cause the generation (disease such as cancer) of human diseases.Therefore
MTOR signal paths are increasingly becoming an important target spot of design cancer therapy drug.
The activation of PI3K/Akt/mTOR signal paths and kinds of tumors generation are closely related, in glioma, breast cancer, ovary
MTOR can speed up the cell cycle in cancer, reduce Apoptosis, and promote the migration of tumour cell.MTOR activation rises
Start from the growth factor receptors on some cell surfaces by ligand activation, such as EGF-R ELISA and insulin-like growth
The factor -1 and -2 (IGF-1 and -2).The activation of acceptor causes the activation of PI3K kinases, so as to cause downstream effect Akt albumen
Activation.Akt be one can on multi-level modulating apoptosis in platelets regulatory factor.Suppress downstream TSC1/2 after Akt phosphorylation to answer
Compound, so as to cause mTOR to be activated by Rheb.Lead in PI3K/Akt and PEN/Akt and Ras/Erk1/2 signal
The downstream on road, TSC1/2 compounds play critical effect for regulation mTOR activation.
Have now found that intracellular in the presence of two kinds of different mTOR protein complexes, mTORC1 and mTORC2.This two
Plant protein complex and include unique protein interacted with mTOR, and each by different mechanism regulatings.
The research and development of mTOR inhibitors medicine have made substantial progress.Rapamycin is first mTOR inhibitors being found,
Preferable cancer resistant effect is shown in kinds cancer model.Although the forms of rapamycin analogs with more preferable pharmacological characteristics is opened
Issue, however, clinically applicable forms of rapamycin analogs is but limited in a few cancer.Akt is cancer cell
Survival an important kinases, and mTORC2 can Direct Phosphorylation Akt, this important mTORC2 that is found to be is in Fighting cancer club
The research in face provides new thinking, while also promoting while acting on the second of two target spots of mTORC1 and mTORC2
For the research and development of cancer therapy drug.Suppress the work of two mTOR complexs (mTORC1 and mTORC2) simultaneously in cancer cell
Property have more extensively and more effective antitumaous effect.
Compound 1, chemical entitled 1- ((1s, 4s) -4- hydroxy-cyclohexyls) -3- methyl -8- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyridine -3-
Base) -1H- imidazos [4,5-c] quinoline -2 (3H) -one is protein kinase PI3K/mTOR double inhibitors, with shown in following formula
Structure：
Compound 1
Compound 1 and its pharmaceutically acceptable salt have been disclosed in WO 2015074516A1, it was reported that it is in cell and moves
Good pharmaceutical activity is shown in thing model.Therefore, exploitation is more stable, be more suitable for preparation and Absorption And Metabolism is preferably changed
The crystal formation of compound 1 is significant to its clinical practice.
The content of the invention
The present invention provides the officinal salt (such as hydrochloride) or the crystal of its hydrate of compound 1 shown in following formula：
Compound 1.
Compound 1 is named as 1- ((1s, 4s) -4- hydroxy-cyclohexyls) -3- methyl -8- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyridine -3-
Base) -1H- imidazos [4,5-c] quinoline -2 (3H) -one.The compound 1 and its preparation method of hydrochloride are recorded in for example
WO2015074516A1 embodiments 18.The full content of the WO2015074516A1 disclosures is by reference simultaneously
Enter herein.
The present invention provides the crystal formation I of the hydrochloride monohydrate of compound 1, it is characterised in that radiated using Cu-K α, with 2 θ
The X-ray powder diffraction characteristic peak that angle (°) is represented can include：9.028±0.2、11.196±0.2、17.393±0.2、
22.504±0.2。
According to the present invention, the crystal formation I is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
Including：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 formation I is radiated using Cu-K α, the X-ray powder diffraction feature represented with 2 θ angles (°)
Peak 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。
Preferably, crystal formation I has Cu-K α radiation X-ray powder diagrams substantially as shown in.
The present invention also provides the crystal formation I of the hydrochloride monohydrate of compound 1 preparation method A, including：
1) it is the hydrochloride of compound 1 is soluble in water；
2) to step 1) solution in add sodium chloride；
3) cool, crystallization is filtered, and is dried, is obtained crystal formation I.
In accordance with the present invention it is preferred that,
Step 1) in, water can be heated before or after the hydrochloride of compound 1 is added, so that the hydrochloride of compound 1 is molten
Solution；Wherein, the consumption of water can be 2~80 times of the hydrochloride weight of compound 1, 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；
Step 2) in, step 1 can kept) at a temperature of solution, add sodium chloride；As example, institute can be controlled
The consumption 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%, for example
3~5%；
The sodium chloride can be its suitable form, for example, can use sodium chloride solution or solid sodium chloride.Preferably, plus
Entering stirring after sodium chloride dissolves it；The sodium chloride solution is preferably sodium-chloride water solution, and the weight percent of wherein sodium chloride contains
Amount can for 10% to saturated concentration, such as 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%,
26%；
Step 3) in, can slow cooling is to less than 60 DEG C (such as 20~50 DEG C) crystallizations under agitation, suction filtration, elution,
15~35 DEG C of (such as 20 DEG C, 25 DEG C, 30 DEG C) vacuum drying, obtain the crystal formation I of the hydrochloride monohydrate of compound 1.
The present invention also provides the crystal formation I of the hydrochloride monohydrate of compound 1 preparation method B, including：
1) hydrochloride of compound 1 is dissolved in ethanol water；
2) cool, crystallization is filtered, and is dried, is obtained crystal formation I.
In accordance with the present invention it is preferred that,
Step 1) in, ethanol water can be heated before or after the hydrochloride of compound 1 is added, so that compound 1
Hydrochloride salt；Wherein, the consumption of ethanol water can be 5~80 times of the hydrochloride weight of compound 1, 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；
In ethanol water the mass percent of ethanol can be such as 30~99%, such as 40~98%, 45~95%, 46~85%,
48~80%, 50~75% or 60~70%；
Step 2) in, can under agitation slow cooling to less than 40 DEG C (such as 20~30 DEG C) crystallizations, suction filtration, 15~35 DEG C
(such as 25 DEG C of room temperature) is dried in vacuo, and obtains the crystal formation I of the hydrochloride monohydrate of compound 1.
The present invention also provides the crystal formation II of the hydrochloride monohydrate of compound 1, it is characterised in that radiated using Cu-K α, with 2 θ
The X-ray powder diffraction characteristic peak that angle (°) is represented can include：8.934±0.2、11.126±0.2、15.367±0.2、
22.437±0.2。
According to the present invention, the crystal formation II is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying 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 formation II is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
Including：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 formation II has Cu-K α radiation X-ray powder diagrams substantially as shown in Figure 8.
The present invention also provides the crystal formation II of the hydrochloride monohydrate of compound 1 preparation method, including：
1) saturated solution of the hydrochloride of compound 1 in two kinds of different solvents is mixed；
2) make step 1) mixture solvent flashing, obtain crystal formation II.
Preparation in accordance with the present invention, it is preferable that
Step 1) in, 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 molten
Agent is selected from organic solvent, is 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 tertiary butyl ether(MTBE), methyl isopropyl ether, methyl ethyl ether, ether), nitrile solvents (such as acetonitrile, propionitrile)；Preferably,
The ratio between described two respective cumulative volumes of saturated solution are 2:1~1:2, such as 1:1；For example, can be by two kinds of saturated solutions 96
Mixed in orifice plate；
Step 2) in, can be by step 1) mixture be placed under atmospheric environment slow solvent flashing；As example, it can lead to
Cross and cover 96 orifice plates with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal formation II.
The present invention also provides the crystal formation III of the hydrochloride of compound 1, it is characterised in that radiated using Cu-K α, with 2 θ angles
The X-ray powder diffraction characteristic peak that (°) is represented can 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 X-ray powder diffraction characteristic peak that the crystal formation III is represented with 2 θ angles (°) can include：
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 formation III has Cu-K α radiation X-ray powder diagrams substantially as shown in Figure 10.
The present invention also provides the hydrochloride Form III of compound 1 preparation method, including：
1) saturated solution of the hydrochloride of compound 1 in two kinds of different solvents is mixed；
2) make step 1) mixture solvent flashing, obtain crystal formation III.
Preparation in accordance with the present invention, it is preferable that
Step 1) in, two kinds of saturated solutions can be mixed below 35 DEG C, at preferably 20~25 DEG C；The solvent choosing
From organic solvent, one of the following is selected from or a variety of：Alcohols solvent (such as methanol, ethanol, normal propyl alcohol, isopropanol,
N-butanol), ether solvent (such as tetrahydrofuran, 1,4- dioxane, methyl tertiary butyl ether(MTBE), methyl isopropyl ether, Methylethyl
Ether, ether)；Preferably, the ratio between respective cumulative volume of described two saturated solutions is 2:1~1:2, such as 1:1；For example, can
Two kinds of saturated solutions are mixed in 96 orifice plates；
Step 2) in, can be by step 1) mixture be placed under atmospheric environment slow solvent flashing；As example, it can lead to
Cross and cover 96 orifice plates with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal formation III.
The present invention also provides the crystal formation IV of the hydrochloride of compound 1, it is characterised in that radiated using Cu-K α, with 2 θ angles
The X-ray powder diffraction characteristic peak that (°) is represented can 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 formation IV is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation IV has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 11.
The present invention also provides the crystal formation IV of the hydrochloride of compound 1 preparation method, including：
1) saturated solution of the hydrochloride of compound 1 in two kinds of different solvents is mixed；
2) make step 1) mixture solvent flashing, obtain crystal formation IV.
Preparation in accordance with the present invention, it is preferable that
Step 1) in, two kinds of saturated solutions can be mixed below 35 DEG C, at preferably 20~25 DEG C；The solvent choosing
From organic solvent, one of the following is selected from 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, described two saturated solutions are each
From the ratio between cumulative volume be 2:1~1:2, such as 1:1；For example, two kinds of saturated solutions can be mixed in 96 orifice plates；
Step 2) in, can be by step 1) mixture be placed under atmospheric environment slow solvent flashing；As example, it can lead to
Cross and cover 96 orifice plates with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal formation IV.
The present invention also provides the crystal formation V of the hydrochloride dihydrate of compound 1, it is characterised in that radiated using Cu-K α, with 2 θ
The X-ray powder diffraction characteristic peak that angle (°) is represented can include：6.181±0.2、8.318±0.2、18.223±0.2、
31.778±0.2。
According to the present invention, the crystal formation V is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation V has substantially Cu-K α radiation X-rays powder diagram as shown in fig. 13 that.
The present invention also provides the crystal formation V of the hydrochloride dihydrate of compound 1 preparation method, including：
1) the salt solution saturated solution of the hydrochloride of prepare compound 1；
2) by step 1) solution place, crystallization, suction filtration obtains crystal formation V.
Preparation in accordance with the present invention, it is preferable that
Step 1) in, the salt solution saturated solution of the hydrochloride of compound 1 is molten for the sodium chloride water saturation of the hydrochloride of compound 1
Liquid；In the saturated solution weight percentage of sodium chloride can for 1% to saturated concentration, such as 1%, 5%, 10%,
12%th, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%, 26%；
Preferably, step 1) saturated solution come from above-mentioned crystal formation I preparation methods step A 3) filtering after mother liquor；
Step 2) in, the solution can be below 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C placement more than 8h,
For example stand overnight, or placement more than 24h, such as more than 36h, more than 48h or more than seven days.
The present invention also provides the crystal formation VI of the hydrochloride dihydrate of compound 1, it is characterised in that radiated using Cu-K α, with
The X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented can 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 formation VI is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation VI has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 15.
The present invention also provides the crystal formation VI of the hydrochloride dihydrate of compound 1 preparation method, including：
1) hydrochloride of compound 1 is dissolved in the mixed liquor of water and acetonitrile；
2) stir, separate out crystal, filter, dry, obtain crystal formation VI.
In accordance with the present invention it is preferred that,
Step 1) in, can be below 40 DEG C, such as it is less than 30 DEG C, such as 20~25 DEG C, the hydrochloride of compound 1 is molten
In the mixed liquor of water and 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%；
Step 2) in, can be below 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C, stir 20 hours, separate out big
White crystal is measured, suction filtration, gained solid obtains crystal formation VI in 25 DEG C of vacuum drying.
The present invention also provides the crystal formation VII of the hydrochloride dihydrate of compound 1, it is characterised in that radiated using Cu-K α, with
The X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented can 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 formation VII is radiated using Cu-K α, the X-ray powder diffraction represented with 2 θ angles (°)
Characteristic peak can 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 formation VII has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 17.
The present invention also provides the crystal formation VII of the hydrochloride dihydrate of compound 1 preparation method A, including：
1) it is the hydrochloride of compound 1 is soluble in water；
2a) by step 1) aqueous solution cooling crystallization；Or 2b) to step 1) the aqueous solution in add sodium chloride, stirring analysis
It is brilliant；
3) filter, dry, obtain crystal formation VII.
Method in accordance with the invention it is preferred that
Step 1) in, the consumption of water is 10~500 times of the hydrochloride weight of compound 1, such as 20~200 times, such as 60 or
180 times；Preferably, water is heated before or after the hydrochloride of compound 1 is added；Preferably, in addition to heat filtering remove
The step of insoluble matter；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 step 1) the aqueous solution be cooled to less than 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C analysis
It is brilliant；
Step 2b) in, below 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C stirring and crystallizings；Sodium chloride can be
Its suitable form, for example, can use sodium chloride solution or solid sodium chloride.Preferably, adding stirring after sodium chloride makes its molten
Solution；For example, the consumption of sodium chloride can be 1~15 times, such as 4~8 times of the hydrochloride of compound 1；
Wherein step 2a) and 2b) to select a progress；
Step 3) in, the filtering can be suction filtration, and the drying can be vacuum drying.
The present invention also provides the crystal formation VII of the hydrochloride dihydrate of compound 1 preparation method B, including：
By the one or more in above-mentioned crystal formation I-VI, carry out DL using water and be beaten 3 days, obtain crystal formation VII.
Preferably, DL mashing is below 40 DEG C in methods described, such as less than 30 DEG C, is carried out at such as 20~25 DEG C；It is mixed
The consumption of rotation mashing reclaimed water is 20~200 times, such as 100 times of crystal formation I-VI gross weights.
The present invention also provides a kind of pharmaceutical composition, includes the one or more in above-mentioned crystal or crystal formation.
According to the present invention, described pharmaceutical composition can also include pharmaceutically acceptable carrier.
Pharmaceutically acceptable carrier is preferably such carrier, and it is under the concentration consistent with the effective active of active component to suffering from
Person's relative nontoxic and harmless, so that any side effect will not destroy the beneficial effect of the active component as caused by the carrier.
The pharmacy effective dose of compound or its pharmaceutically acceptable salt is preferably to produce result or generation to the specific patient's condition treated
The amount of influence.Any effective conventional dosage unit forms including quick-release, sustained release and time release formulation can be used, will
The compound of the present invention is administered as follows together with pharmaceutically acceptable carrier well known in the art：Orally, parenteral,
Part, nasal cavity, eye, sublingual, rectum, vagina administration etc..
For being administered orally, the compound or its pharmaceutically acceptable salt can be configured to solid or liquid preparation, such as glue
Wafer, pill, tablet, containing lozenge (troche), lozenge (lozenge), melten gel agent (melt), powder, solution, mixed
Suspension or emulsion, and can be prepared according to known in the art for preparing the method for pharmaceutical composition.Solid unit dosage form can
For capsule, it can be common ebonite bladder type or soft-capsule type, include such as surfactant, lubricant and inert filler
(such as lactose, sucrose, calcium phosphate and cornstarch).
In another embodiment, can be by the compound or its pharmaceutically acceptable salt and conventional tablet bases of the present invention (for example
Lactose, sucrose and cornstarch) it is together and tabletted with following combinations of substances：Adhesive (such as Arabic gum, corn
Starch or gelatin), for tablet after adjunctive administration decomposition and dissolution disintegrant (such as potato starch, alginic acid, cornstarch
With guar gum, gum tragacanth, Arabic gum), the mobility for improving tablet granulation and prevent tablet material and tablet mould
With the lubricant (such as talcum, stearic acid or magnesium stearate, calcium stearate or zinc stearate) of the surface adhesion of drift, dyestuff,
Colouring agent, and for improve the organoleptic properties of tablet and make flavor enhancement that they are easier to be accepted by patients (such as peppermint oil,
Wintergreen or cherry essence).Suitable excipient for oral liquid dosage forms includes Dicalcium Phosphate and diluent, such as water and alcohol
(such as ethanol, phenmethylol and polyvinyl alcohol), diluent addition or without have pharmaceutically acceptable surfactant,
Suspending agent or emulsifying agent.There may be various other materials as being coated or the physical form for changing dosage unit.For example
Can with shellac, sugar or the two by tablet, pill or capsule be coated.
Also the compound of the present invention with the injection of the compound can be subjected to parenteral, i.e., subcutaneous, intravenous, intraocular,
Intrasynovial, intramuscular or Intraperitoneal medication, the injection preferably in the acceptable diluent of the physiology containing pharmaceutical carrier,
The pharmaceutical carrier can be sterile liquid or the mixture of liquid, and the liquid is such as water, salt solution, D/W and phase
The sugar juice of pass, alcohol such as ethanol, isopropanol or hexadecanol, glycol such as propane diols or polyethylene glycol, glycerol ketals such as 2,2-
Dimethyl -1,1- dioxolanes -4- methanol, ether such as polyethylene glycol 400 (PEG400), oil, aliphatic acid, fatty acid ester or fat
Fatty acid glyceride or acetylated fatty acid glyceride, diluent addition or without there is pharmaceutically acceptable surfactant,
Such as soap or detergent, suspending agent such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose,
Or emulsifying agent and other pharmaceutical auxiliaries.
Exemplary surfactants for parenteral administration are polyethylene sorbitan fatty acid ester, such as anhydrosorbitol
Sorbitane monooleate, and oxirane and hydrophobic base high molecular weight adducts, the hydrophobic base is by expoxy propane
It is condensed to be formed with propane diols.
The composition of the present invention can be also administered for the form of the suppository of the rectally of medicine.Can by by medicine with normal
Under temperature it is solid but therefore can dissolves for liquid and in the rectum under rectal temperature and discharge the suitable stingless of the medicine
The excipient for swashing property mixes to prepare these compositions.Such material is such as cocoa butter and polyethylene glycol.
Controlled release preparation for parenteral includes liposome microballoon known in the art, polymer microballoon and polymer gel system
Agent.
It may need or described pharmaceutical composition must be delivered to by patient by mechanical delivery device.Machinery for delivering medicament
The construction and purposes of delivery apparatus are well known in the art.The direct technology that medicine for example is administered directly into brain is usually directed to medicine
Thing delivery catheter inserts the ventricular system of patient to bypass 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, wherein described
Combination will not cause unacceptable adverse reaction.The invention further relates to such combination.For example, can by the present invention compound with
Known chemotherapeutics or anticancer (such as anti-excess proliferative disease or the medicament of other indications) and the mixing with them
Thing and combination are combined.Other indication medicaments include but is not limited to anti-angiogenic agent, mitotic inhibitor, alkylating agent,
Antimetabolite, DNA- insertions antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topoisomerase suppression
Preparation, biological response modifier or antihormones.
The present invention also provides the one or more in the crystal formation, and it is used to treat or prevent the disease related to protein kinase activity.
The method that the present invention also provides regulation (as lower) protein kinase activity, including by the protein kinase and effective dose
Above-mentioned crystal formation in one or more contacts.This method can be used in vivo, can be used for external.Preferably, the egg
White kinases is selected from least one of mTOR and PI3K.
According to further aspect of the application, this application provides a kind of method for treating the disease related to protein kinase activity,
Methods described includes being applied to the one or more in the above-mentioned crystal formation of effective dose into the individual of this demand.The individual can be
Mammal, such as mankind.
The disease related to protein kinase activity described in this specification is (such as by suppressing one kind or two in mTOR and PI3K
The disease for planting kinases to treat or prevent) can be tumour, such as leukaemia, malignant lymphoma, Huppert's disease, stomach and intestine
Road mesenchymoma, colon and rectum carcinoma, breast cancer, liver cancer, stomach cancer, oophoroma, uterine cancer, cervical carcinoma, carcinoma of vagina, suede
Trichilemma cancer, lung cancer, kidney, prostate cancer, carcinoma of urinary bladder, cancer of pancreas, spongioblastoma, mast cell tumor, brain tumor,
Germinoma, melanoma, sarcoma, including dermatofibrosarcoma protuberans, osteosarcoma.Described herein and egg
The related disease of white kinase activity can also be that metabolic disease (such as diabetes, obesity) and angiocardiopathy (are for example moved
Pulse atherosclerosis).
The one or more that the present invention is also provided in the crystal formation are used for the purposes for preparing the medicine for treating or preventing disease or illness,
The disease or illness can be the diseases or illness related to protein kinase activity, for example including can by suppress mTOR and
One or two kinds of kinases are come the disease that treats or prevents in PI3K.
The one or more that the present invention is also provided in the crystal formation, which are used to prepare, suppresses one or two kinds of in mTOR and PI3K kinases
Medicine in purposes.
The disease is included by uncontrolled cell growth, propagation and/or survival, unsuitable cellullar immunologic response or inappropriate
Cellular inflammation response caused by disease, or with uncontrolled cell growth, propagation and/or survival, unsuitable cell
Immune response or the disease of unsuitable cellular inflammation response, especially, the disease be such as neoplastic hematologic disorder, solid tumor and/
Or their transfer, such as leukaemia and myelodysplastic syndrome, malignant lymphoma, the head including brain tumor and brain metastes
Portion and tumor colli, the breast tumor including non-fire power and small cell lung tumor, gastroenteric tumor, endocrine
Tumour, tumor of breast and other gynecological tumors, the Patients with Urinary System Tumors including kidney neoplasms, bladder knurl and prostate tumor, skin
Skin tumour and sarcoma, and/or their transfer.
The present invention also provides the medicine of hyperproliferative disorders of the compound of the present invention and combinations thereof preparing treatment mammal
In purposes.Cell propagation and/or the cell division such as it can suppress, block, reduce, reducing using compound and/or causing apoptosis.
Hyperproliferative disorders include but is not limited to psoriasis, keloid and other cutaneous hyperplasia, benign prostatic hyperplasis
(BpH), solid tumor for example breast cancer, respiratory cancer, lung cancer, the cancer of the brain, genital cancer, digestive system cancer, the urinary tract cancer,
Cancer eye, liver cancer, cutaneum carcinoma, head and neck cancer, thyroid cancer, parathyroid carcinoma and their far-end transfer.The illness is also wrapped
Include lymthoma, sarcoma and leukaemia.
" metabolic disease " used herein refers to the disease caused by metabolic problems, including dysbolism and is metabolized the reason such as vigorous,
Mainly include these following diseases：Diabetes, diabetic ketoacidosis, hyperglycaemia hyperosmolality syndrome, hypoglycemia, gout,
Protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis etc..
" angiocardiopathy " used herein is also known as circulation system disease, is a series of diseases for being related to the circulatory system, cyclic system
System refers to hemophoric organ and tissue in human body, mainly including heart, blood vessel (artery, vein, capilary), can segment
It is typically all relevant with artery sclerosis to be acute and chronic.Angiocardiopathy includes：Heart disease, low blood pressure, hypertension, height
Blood glucose disease, apoplexy, miocardial infarction, thrombus, artery sclerosis etc..
These illnesss obtain good sign in the mankind, but are also present in similar teiology in other mammals,
And it can be treated by the way that the pharmaceutical composition of the present invention is administered.
In some embodiments, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release preparation,
Solution and suspension, for the sterile solution, suspension or emulsion of parental injection, for the ointment or emulsifiable paste of external application, or
Suppository for rectally.In other embodiments, described pharmaceutical composition is to be adapted to the unit that single bestows exact dose
Formulation.In other embodiments, the amount of the compound is in about 0.001mg/kg body weight/days-about 1000mg/kg body weight/days
In the range of.In other embodiments, the scope of the amount of the compound is about 0.5mg/kg body weight/days-about 50mg/kg body weight
/ day.In some embodiments, the amount of the compound is about 0.001g/ days-about 7g/ days.In other embodiments, it is described
The amount of compound is about 0.002g/ days-about 6g/ days.In other embodiments, the amount of the compound be 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 embodiments, institute
The amount for stating compound is about 0.02g/ days-about 5g/ days.In other embodiments, the amount of the compound be about 0.05g/ days-about
2.5g/ my god.In other embodiments, the amount of the compound is about 0.1g/ days-about 1g/ days.In other embodiments, it is low
In the dosage level of above range lower limit may be enough.In other embodiments, it may be necessary to higher than above range
The dosage level of the upper limit.In some embodiments, the compound is applied with single dose, once a day.In other embodiment party
In formula, the compound is applied with multiple dose, daily more than once.In some embodiments, describedization twice is applied daily
Compound.In other embodiments, three compounds are applied daily.In other embodiments, four institutes are applied daily
State compound.In other embodiments, the daily compound for applying more than four times.In some embodiments, it is described
The individual that pharmaceutical composition is applied to is mammal.In other embodiments, the mammal is people.Implement other
In mode, described pharmaceutical composition is also comprising a kind of at least one therapeutic agent (formulation is made).In some embodiments, institute
Pharmaceutical composition and at least one therapeutic agent are stated respectively with independent dosage form combination into combination product, such as set containing medicines (kitofpart).
The crystal formation that the present invention is provided has good stability, is included under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation and has
There is good stability, and also keep in tableting processes good stability.The crystal formation that the present invention is provided has good body
Interior Absorption And Metabolism property, including blood concentration, Drug-time curve AUC, half-life period etc..Moreover, the crystal formation dissolution velocity of the present invention
Improved, be conducive to the application on preparation.
Technical term of pharmacology
Some technical term of pharmacology relevant term " subject ", " patient " or " individual " used herein refers to suffer from disease, illness or disease
The individual of condition etc., including mammal and nonmammalian.The embodiment of mammal includes but is not limited to appointing for class of mammals
What member：People, inhuman primate (such as chimpanzee and other apes and monkey)；Domestic animal, such as ox, horse, sheep,
Goat, pig；Domestic animal, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and
Cavy etc..The embodiment of non-human mammal includes but is not limited to birds and fish etc..Provided herein is a method and
In the embodiment of composition, the mammal is behaved.
Term " treatment " used herein includes alleviating with other similar synonyms, mitigates or improve disease or condition symptoms, in advance
Prevent other symptoms, improve or prevention causes the potential metabolism reason of symptom, suppress disease or illness, for example, prevent disease or illness
Development, alleviate disease or illness, disease or illness is taken a turn for the better, alleviate the symptom caused by disease or illness, or stop disease
The symptom of disease or illness, in addition, the term includes the purpose of prevention.The term also includes obtaining therapeutic effect and/or preventive effect.
The therapeutic effect refers to cure or improves treated potential disease.In addition, raw to the one or more related to potential disease
The healing or improvement for managing symptom are also therapeutic effect, although for example patient may nevertheless suffer from the influence of potential disease, are observed
Patient profiles improve., can be to the patient's applying said compositions for suffering from specified disease risk, or i.e. for preventive effect
Just medical diagnosis on disease is not yet made, but to the patient's applying said compositions for one or more physiological signs of the disease occur.
Term " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with to a certain extent
At least one medicament or the amount of compound of one or more symptoms of the treated disease of alleviation or illness.Its result can be mark
As abatement and/or the alleviation of, symptom or the cause of disease, or biosystem it is any other needed for change.For example, " having for treatment
Effect amount " is clinically to provide the amount for including the composition that compound is disclosed herein needed for significant remission effect.It can be used
The technology of such as dose escalation trial determines the effective dose being suitable in any individual case.
Terms used herein " taking ", " administration ", " administration " etc. are to refer to compound or composition being delivered to the biological work of progress
The method in required site.These methods include but is not limited to oral route, through intraduodenal routes, parental injection (including
Intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Those skilled in the art are ripe
Know the application technique available for Compounds and methods for described herein, such as in Goodman and Gilman, The
Pharmacological Basis of Therapeutics,current ed.；Pergamon and Remington's,
Those discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
In preferred embodiment, the compound and composition being discussed herein are by orally administering.
Refer to the general health for docking treated subject herein for term " acceptable " used in preparation, composition or composition
Situation does not have long-term adverse effect.
Brief description of the drawings
Fig. 1 uses the alpha-emitting X-ray powder diffractions of Cu-K (XRPD) spectrogram for crystal formation I in embodiment I-1.
Thermogravimetic analysis (TGA) (TGA) spectrogram that Fig. 2 is crystal formation I in embodiment I-1.
Means of differential scanning calorimetry (DSC) spectrogram that Fig. 3 is crystal formation I in embodiment I-1.
Fig. 4 is the XRPD spectrograms of crystal formation I solids under the conditions of 60 DEG C in embodiment I-4.
Fig. 5 is the XRPD spectrograms of crystal formation I solids under the conditions of 25 DEG C/90%RH in embodiment I-4.
Fig. 6 is the XRPD spectrograms of crystal formation I solids under illumination condition in embodiment I-4.
Fig. 7 is the XRPD comparison diagrams before and after crystal formation I tablettings in embodiment I-5.
The XRPD spectrograms that Fig. 8 is crystal formation II in embodiment II-1.
The TGA spectrograms that Fig. 9 is crystal formation II in embodiment II-1.
The XRPD spectrograms that Figure 10 is crystal formation III in embodiment III-1.
The XRPD spectrograms that Figure 11 is crystal formation IV in embodiment IV-1.
The TGA spectrograms that Figure 12 is crystal formation IV in embodiment IV-1.
The XRPD spectrograms that Figure 13 is crystal formation V in embodiment V-1.
The TGA spectrograms that Figure 14 is crystal formation V in embodiment V-1.
The XRPD spectrograms that Figure 15 is crystal formation VI in embodiment VI-1.
The TGA spectrograms that Figure 16 is crystal formation VI in embodiment VI-1.
The XRPD spectrograms that Figure 17 is crystal formation VII in embodiment VII-1.
The TGA spectrograms that Figure 18 is crystal formation VII in embodiment VII-1.
Means of differential scanning calorimetry (DSC) spectrogram that Figure 19 is crystal formation VII in embodiment VII-1.
Embodiment
Technical scheme is described in detail by the following examples, to be better understood from technical scheme
And essence.The exemplary only description of the embodiment, is not construed as limiting the scope of the invention.This area skill
Modification or change of the art personnel according to made by the content of the invention and following examples are encompassed by the scope of protection of present invention.
X-ray powder diffraction is determined by Bruker D8advance type X-ray powder diffractions instrument in following examples,
Apparatus preparation LynxEye detectors.2 θ scanning angles of sample are that scanning step is 0.02 ° from 3 ° to 40 °, pipe electricity
Pressure and tube current are respectively 40KV and 40mA.The sample disc that sample measurement is used is zero Background Samples disk.
Means of differential scanning calorimetry (DSC) analysis in following examples is carried out using TA DSC Q200, and it corrects the mark used
Quasi- sample is indium.2-3mg samples are placed in after being precisely weighed in TA DSC sample discs, and record the exact mass of sample.Sample
Product are heated to 200-250 DEG C in 50mL/min nitrogen stream with 10 DEG C/min heating rate.Heat in following examples
Weight analysis are carried out using TA TGA Q500.2-3mg samples are placed in Balanced aluminum sample disk, and sample quality is in TGA
Automatic weighing in heating furnace.Sample is heated to 200-300 DEG C with 10 DEG C/min speed.In test process, nitrogen is to balance
The nitrogen flow of room and sample room is 40mL/min and 60mL/min respectively.
Unless otherwise indicated, in following examples raw material, substrate or reagent is that commercially available commodity are (such as used anhydrous
Ethanol is the commercially available pure absolute ethyl alcohol of analysis), it can also be prepared by methods known in the art.
It is prepared by embodiment I-1 crystal formations I
The hydrochloride 96g of compound 1 is dissolved in the 860ml water of 100 DEG C of bath temperature, 43g solid sodium chlorides are added while hot, are stirred
Mixing down dissolves it, slow cooling to 30 DEG C of crystallizations, and suction filtration simultaneously uses 100ml water wash, and gained solid is dry in 25 DEG C of vacuum
It is dry, the crystallization of 86g yellow greens is obtained, is after tested the crystal formation I of the hydrochloride monohydrate of compound 1.
It is prepared by embodiment I-2 crystal formations I
In the 2L water that the hydrochloride 110g of compound 1 is dissolved in 100 DEG C of bath temperature, 100g sodium chloride is added while hot in 500ml
Solution in water, the lower slow cooling of stirring is to 20 DEG C of crystallizations, and suction filtration simultaneously use 100ml water wash, solid at 30 DEG C very
Sky is dried, and is obtained the crystallization of 97g yellow greens, is after tested the crystal formation I of the hydrochloride monohydrate of compound 1.
It is prepared by embodiment I-3 crystal formations I
In the mixed liquor that the hydrochloride 0.5g of compound 1 is dissolved in the 10ml ethanol of 85 DEG C of bath temperature and 5.5ml water, under stirring
Naturally cool to 25 DEG C of crystallizations, suction filtration, solid in 25 DEG C of vacuum drying, the crystallization of 0.36g yellow greens is obtained, through surveying
Try as the crystal formation I of the hydrochloride monohydrate of compound 1.
Embodiment I-4 crystal formation I stability experiments
The crystal formation I of the hydrochloride monohydrate of compound 1 in a small amount of embodiment I-1 is taken, is respectively put into stability of drug products experimental box,
Condition listed by control table 1 carries out stability experiment, and purity and content acquired results are listed in Table I -1, and crystal formation test result is such 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, crystal formation I compound purity and content
Have no significant change (purity is floated within 0.2%, and content is floated within 1%), it was demonstrated that crystal formation I stability is preferable.
As shown in Figures 4 to 6, under three kinds of extreme conditions such as high temperature, high humidity and intense light irradiation, crystal formation I keeps crystal formation unchanged,
The stability for demonstrating crystal formation I is preferable.
The crystal formation I stability experimental results of Table I -1
Embodiment I-5 crystal formation I tabletting stability experiments
The crystal formation I of the hydrochloride monohydrate of compound 1 in a small amount of embodiment 1 is taken, a diameter of 8mm tablet is pressed into manually,
Then tablet is gently pulverized, powder carries out XRPD analyses, and result is contrasted with the XRPD results before tabletting, such as
Shown in fruit Fig. 7, to investigate, tableting processes are no to produce influence to crystal formation.The XRPD collection of illustrative plates of powder before and after crystal formation I tablettings is entered
Contrast is gone, has as a result shown, tableting processes are to crystal formation I without change, and the XRPD collection of illustrative plates of powder is identical before and after tabletting.
Embodiment I-6 crystal formations I SD Oral Administration in Rats administration metabolism
By being suspended in 5.274mL 0.5% sodium carboxymethylcellulose for the 11.392mg crystal formations I hydrochloride of compound 1,
It is vortexed, forms homogeneous suspension, ultrasound 2min is finally made homogeneous suspension solution (the administration same day that concentration is 2mg/mL afterwards
Matching while using, storage is no more than 4 hours).To three SD rats press 10mg/kg body weight dose gastric infusions, by setting when
Between point take haemanalysis, acquired results are listed in the table below I-2：
Table I -2：Crystal formation I rat oral gavage drug metabolism experimental datas
From Table I -2 it is known that after crystal formation I drug administration, highest blood concentration (Cmax) up to 14600ng/ml,
AUC last are up to 190696h*ng/mL, and this is very high numerical value in drug metabolism, while 5.5h half-life period is also
More satisfactory numerical value in drug metabolism, it is well-behaved that these all demonstrate the Absorption And Metabolism of crystal formation I medicine in animal body.
It is prepared by embodiment II-1 crystal formations II
At room temperature, by each 100 microlitres of the ethyl acetate saturated solution and 2- butanone saturated solutions of the hydrochloride of compound 1, in 96
Mixed in orifice plate, covered with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal, passed through
Test as the crystal formation II of the hydrochloride monohydrate of compound 1.
It is prepared by embodiment II-2 crystal formations II
At room temperature, by each 100 microlitres of the tetrahydrofuran saturated solution and acetonitrile saturated solution of the hydrochloride of compound 1, in 96 holes
Mixed in plate, covered with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal, through surveying
Try as the crystal formation II of the hydrochloride monohydrate of compound 1.
It is prepared by embodiment II-3 crystal formations II
At room temperature, by each 100 microlitres of the tetrahydrofuran saturated solution and acetone saturated solution of the hydrochloride of compound 1, in 96 holes
Mixed in plate, covered with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal, through surveying
Try as the crystal formation II of the hydrochloride monohydrate of compound 1.
It is prepared by embodiment III-1 crystal formations III
At room temperature, by each 100 microlitres of the alcohol saturated solution and isopropanol saturated solution of the hydrochloride of compound 1, in 96 orifice plates
Interior mixing, is covered with the sealed membrane for pricking hole, is placed in fume hood, is volatilized naturally under atmospheric environment, obtain crystal, after tested
For the crystal formation III of the hydrochloride of compound 1.
It is prepared by embodiment III-2 crystal formations III
At room temperature, by each 100 microlitres of the isopropanol saturated solution and methyl tertiary butyl ether(MTBE) saturated solution of the hydrochloride of compound 1, in
Mixed in 96 orifice plates, covered with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal,
It is the crystal formation III of the hydrochloride of compound 1 after tested.
It is prepared by embodiment IV-1 crystal formations IV
At room temperature, by each 100 microlitres of the toluene saturated solution and isobutyl acetate saturated solution of the hydrochloride of compound 1, in 96
Mixed in orifice plate, covered with the sealed membrane for pricking hole, be placed in fume hood, volatilized naturally under atmospheric environment, obtain crystal, passed through
Test as the crystal formation IV of the hydrochloride of compound 1.
It is prepared by embodiment V-1 crystal formations V
Example I-1 mother liquor is placed more than 48 hours for a long time at 20~25 DEG C, white crystals are separated out, suction filtration obtains crystalline substance
Body, is after tested the crystal formation V of the hydrochloride dihydrate of compound 1.
It is prepared by embodiment V-2 crystal formations V
Example I-2 mother liquor is placed for a long time at 20~25 DEG C, white crystals are separated out, suction filtration obtains crystal, after tested for
The crystal formation V of the hydrochloride dihydrate of compound 1.
It is prepared by embodiment VI-1 crystal formations VI
By the hydrochloride 0.5g of compound 1 in 20~25 DEG C of mixed liquors for being dissolved in 50ml water and 20ml acetonitriles, room temperature is stirred
Mix 20 hours, separate out a large amount of white crystals, suction filtration, gained solid obtains 0.27g white crystals in 25 DEG C of vacuum drying,
It is the crystal formation VI of the hydrochloride dihydrate of compound 1 after tested.
It is prepared by embodiment VII-1 crystal formations VII
The hydrochloride 0.5g of compound 1 is dissolved in and is heated to 90 DEG C of 90ml water, room temperature (20~25 DEG C) is cooled to, stirred
Lower addition 3g sodium chloride, is stirred at room temperature 20 hours, a large amount of white-yellowish solids of precipitation, suction filtration, and gained solid is in 25 DEG C of vacuum
Dry, obtain 0.46g white crystals, be after tested the crystal formation VII of the hydrochloride dihydrate of compound 1.
It is prepared by embodiment VII-2 crystal formations VII
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
Thing, naturally cools to room temperature (20~25 DEG C) under mother liquor stirring, suction filtration, gained solid obtains 0.21g in 25 DEG C of vacuum drying
White crystals, are after tested the crystal formation VII of the hydrochloride dihydrate of compound 1.
It is prepared by embodiment VII-3 crystal formations VII
By above-mentioned crystal formation I, 10mg is taken, 1ml water is added, 20~25 DEG C of DLs are beaten 3 days, white crystals are obtained, through surveying
Try as the crystal formation VII of the hydrochloride dihydrate of compound 1.
It is prepared by embodiment VII-4 crystal formations VII
One kind in above-mentioned crystal formation II, III, IV, V, VI is replaced with according to embodiment VII-3, but by crystal formation I, is obtained
Crystal formation VII.
Embodiment VII-5 crystal formations VII dissolution velocity test
Weigh respectively in taking crystal formation VII, crystal formation I, each 3mg of crystal formation VI, the plastic centrifuge tube for being respectively put into 3 1ml,
Often pipe plus 1ml distilled water, rock in 20~25 DEG C and are placed after 5 seconds, observe dissolution phenomena：
Crystal formation VII whole dissolved clarifications in 10 seconds；
Crystal formation I basic dissolved clarifications in 2 hours, whole dissolved clarifications in 5 hours；
Crystal formation VI non-dissolved clarifications after 5h.
As can be seen here, crystal formation VII is instant crystal formation, has good application value in terms of Expidet is made.
Claims (12)
1. the officinal salt (such as hydrochloride) or the crystal of its hydrate of compound 1 shown in following formula：
2. the crystal described in claim 1, it is the crystal formation I of the hydrochloride monohydrate of compound 1, it is characterised in that used
Cu-K α are radiated, and can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented：9.028±0.2、11.196±0.2、
17.393±0.2、22.504±0.2；
For example, the crystal formation I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°) can be with
Including：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 formation I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak bag represented 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 formation I is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
Including：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 formation I has Cu-K α radiation X-ray powder diagrams substantially as shown in.
3. the crystal described in claim 1, it is the crystal formation II of the hydrochloride monohydrate of compound 1, it is characterised in that used
Cu-K α are radiated, and can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented：8.934±0.2、11.126±0.2、
15.367±0.2、22.437±0.2；
Preferably, the crystal formation II is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
Including：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 formation II is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
Including：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 formation II has Cu-K α radiation X-ray powder diagrams substantially as shown in Figure 8.
4. the crystal described in claim 1, it is the crystal formation III of the hydrochloride of compound 1, it is characterised in that use Cu-K α
Radiation, can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented：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；
Preferably, the X-ray powder diffraction characteristic peak that the crystal formation III is represented with 2 θ angles (°) can include：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 formation III has Cu-K α radiation X-ray powder diagrams substantially as shown in Figure 10.
5. the crystal described in claim 1, it is the crystal formation IV of the hydrochloride of compound 1, it is characterised in that use Cu-K α
Radiation, can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented：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；
Preferably, the crystal formation IV is radiated using Cu-K α, the X-ray powder diffraction characteristic peak represented with 2 θ angles (°)
It can 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 formation IV has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 11.
6. the crystal described in claim 1, it is the crystal formation V of the hydrochloride dihydrate of compound 1, it is characterised in that used
Cu-K α are radiated, and can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented：6.181±0.2、8.318±0.2、
18.223±0.2、31.778±0.2；
According to the present invention, the crystal formation V is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation V has substantially Cu-K α radiation X-rays powder diagram as shown in fig. 13 that.
7. the crystal described in claim 1, it is the crystal formation VI of the hydrochloride dihydrate of compound 1, it is characterised in that made
Radiated, can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented with Cu-K α：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 formation VI is radiated using Cu-K α, special with the X-ray powder diffraction that 2 θ angles (°) are represented
Levying peak can 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 formation VI has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 15.
8. the crystal described in claim 1, it is the crystal formation VII of the hydrochloride dihydrate of compound 1, it is characterised in that made
Radiated, can be included with the X-ray powder diffraction characteristic peak that 2 θ angles (°) are represented with Cu-K α：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 formation VII is radiated using Cu-K α, the X-ray powder diffraction represented with 2 θ angles (°)
Characteristic peak can 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 formation VII has Cu-K α radiation X-ray powder diagrams substantially as shown in figure 17.
9. the preparation method of crystal described in claim 2, one kind in following preparation method A or preparation method B：
Preparation method A, including：
1) it is the hydrochloride of compound 1 is soluble in water；
2) to step 1) solution in add sodium chloride；
3) cool, crystallization is filtered, and is dried, is obtained crystal formation I；
Preferably,
Step 1) in, water can be heated before or after the hydrochloride of compound 1 is added, so that the hydrochloride of compound 1 is molten
Solution；Wherein, the consumption of water can be 2~80 times of the hydrochloride weight of compound 1, 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；
Step 2) in, step 1 can kept) at a temperature of solution, add sodium chloride；As example, institute can be controlled
The consumption 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%, for example
3~5%；
The sodium chloride can be its suitable form, for example, can use sodium chloride solution or solid sodium chloride.Preferably, plus
Entering stirring after sodium chloride dissolves it；The sodium chloride solution is preferably sodium-chloride water solution, and the weight percent of wherein sodium chloride contains
Amount can for 10% to saturated concentration, such as 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%,
26%；
Step 3) in, can slow cooling is to less than 60 DEG C (such as 20~50 DEG C) crystallizations under agitation, suction filtration, elution,
15~35 DEG C of (such as 20 DEG C, 25 DEG C, 30 DEG C) vacuum drying, obtain the crystal formation I of the hydrochloride monohydrate of compound 1；
Or,
Preparation method B, including：
1) hydrochloride of compound 1 is dissolved in ethanol water；
2) cool, crystallization is filtered, and is dried, is obtained crystal formation I；
Preferably,
Step 1) in, ethanol water can be heated before or after the hydrochloride of compound 1 is added, so that compound 1
Hydrochloride salt；Wherein, the consumption of ethanol water can be 5~80 times of the hydrochloride weight of compound 1, 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；
In ethanol water the mass percent of ethanol can be such as 30~99%, such as 40~98%, 45~95%, 46~85%,
48~80%, 50~75% or 60~70%；
Step 2) in, can under agitation slow cooling to less than 40 DEG C (such as 20~30 DEG C) crystallizations, suction filtration, 15~35 DEG C
(such as 25 DEG C of room temperature) is dried in vacuo, and obtains the crystal formation I of the hydrochloride monohydrate of compound 1.
10. the preparation method of crystal described in claim 8, one kind in following preparation method A or preparation method B：
Preparation method A, including：
1) it is the hydrochloride of compound 1 is soluble in water；
2a) by step 1) aqueous solution cooling crystallization；Or 2b) to step 1) the aqueous solution in add sodium chloride, stirring analysis
It is brilliant；
3) filter, dry, obtain crystal formation VII；
Preferably,
Step 1) in, the consumption of water is 10~500 times of the hydrochloride weight of compound 1, such as 20~200 times, such as 60 or
180 times；Preferably, water is heated before or after the hydrochloride of compound 1 is added；Preferably, in addition to heat filtering remove
The step of insoluble matter；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 step 1) the aqueous solution be cooled to less than 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C analysis
It is brilliant；
Step 2b) in, below 40 DEG C, such as less than 30 DEG C, such as 20~25 DEG C stirring and crystallizings；Sodium chloride can be
Its suitable form, for example, can use sodium chloride solution or solid sodium chloride.Preferably, adding stirring after sodium chloride makes its molten
Solution；For example, the consumption of sodium chloride can be 1~15 times, such as 4~8 times of the hydrochloride of compound 1；
Step 3) in, the filtering can be suction filtration, and the drying can be vacuum drying；
Or,
Preparation method B, including：
By the one or more in above-mentioned crystal formation I-VI, carry out DL using water and be beaten 3 days, obtain crystal formation VII.
Preferably, DL mashing is below 40 DEG C in methods described, such as less than 30 DEG C, is carried out at such as 20~25 DEG C；It is mixed
The consumption of rotation mashing reclaimed water is 20~200 times, such as 100 times of crystal formation I-VI gross weights.
11. pharmaceutical composition, includes the one or more in any one of the claim 1-8 crystal.
12. any one of the claim 1-8 crystal is used for the purposes for preparing the medicine for treating or preventing disease, particularly for making
Purposes in standby suppression mTOR and PI3K kinases in one or two kinds of medicines.
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| CN102399218A (en) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药（上海）有限公司 | Triheterocyclic compounds and their use as PI3K inhibitors |
| WO2015074516A1 (en) * | 2013-11-20 | 2015-05-28 | 北京富龙康泰生物技术有限公司 | Ketone derivatives of imidazoles, pharmaceutical combinations and uses thereof |
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| WO2015074516A1 (en) * | 2013-11-20 | 2015-05-28 | 北京富龙康泰生物技术有限公司 | Ketone derivatives of imidazoles, pharmaceutical combinations and uses thereof |
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| CN113304138A (en) * | 2021-06-30 | 2021-08-27 | 贵州医科大学 | Application of Vitisinol D in preparation of xanthine oxidase inhibition drugs |
| CN113304138B (en) * | 2021-06-30 | 2022-04-29 | 贵州医科大学 | Application of Vitisinol D in preparation of xanthine oxidase inhibition drugs |
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