WO2017128042A1 - 咪唑酮类化合物的晶型、其制备方法、药物组合物和用途 - Google Patents

咪唑酮类化合物的晶型、其制备方法、药物组合物和用途 Download PDF

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WO2017128042A1
WO2017128042A1 PCT/CN2016/072179 CN2016072179W WO2017128042A1 WO 2017128042 A1 WO2017128042 A1 WO 2017128042A1 CN 2016072179 W CN2016072179 W CN 2016072179W WO 2017128042 A1 WO2017128042 A1 WO 2017128042A1
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compound
radiation
ray powder
powder diffraction
hydrochloride
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PCT/CN2016/072179
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English (en)
French (fr)
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季奇
杜镇建
张兴民
王磊
高聪敏
巩龙龙
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北京富龙康泰生物技术有限公司
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Priority to US16/064,242 priority Critical patent/US10646483B2/en
Priority to EP16886929.5A priority patent/EP3412291B1/en
Priority to PCT/CN2016/072179 priority patent/WO2017128042A1/zh
Publication of WO2017128042A1 publication Critical patent/WO2017128042A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to a crystal form of an imidazolidone compound having PI3K/mTOR dual inhibitory activity, a preparation method thereof, a pharmaceutical composition and use thereof, and belongs to the field of crystalline compounds of pharmaceutical compounds.
  • the mammalian target of rapamycin is an atypical serine/threonine protein kinase belonging to the phosphoinositide 3-kinase (PI3K)-related kinase family and is synthesized and decomposed intracellularly.
  • the main signaling molecule for cellular functions such as metabolism.
  • the mTOR signaling pathway is closely related to nutrition, energy status and growth factors. It regulates multiple cellular processes including autophagy, proteins, lipids, lysosomal synthesis and energy metabolism, cytoskeletal organization, and cell survival. Under the changing nutrient conditions of mammalian cells, mTOR regulates the conversion of synthesis and degradation metabolism, allowing cells to grow and survive under different nutritional conditions. Due to the important role of mTOR in cells, abnormal or dysregulated mTOR signaling can lead to the development of human diseases (eg diseases such as cancer). Therefore, the mTOR signaling pathway has gradually become an important target for the design of anticancer drugs.
  • Akt PI3K/Akt/mTOR signaling pathway
  • mTOR can accelerate cell cycle, reduce apoptosis and promote tumor cell migration.
  • Activation of mTOR begins with growth factor receptors on the surface of some ligand-activated cells, such as the epidermal growth factor receptor and insulin-like growth factor-1 and -2 (IGF-1 and -2).
  • IGF-1 and -2 insulin-like growth factor-1 and -2
  • Akt is a regulator that regulates cell survival at multiple levels.
  • Akt Phosphorylation of Akt inhibits the downstream TSC1/2 complex, resulting in mTOR being activated by Rheb. Downstream of the PI3K/Akt and PEN/Akt and Ras/Erk1/2 signaling pathways, the TSC1/2 complex plays a key role in regulating mTOR activation.
  • mTORC1 and mTORC2 Two different mTOR protein complexes, mTORC1 and mTORC2, have been found in cells. These two protein complexes contain unique proteins that interact with mTOR and are each regulated by a different mechanism. Significant progress has been made in the development of mTOR inhibitor drugs. Rapamycin was the first mTOR inhibitor to be discovered and showed good anti-cancer effects in various cancer models. Although rapamycin analogues with better pharmacological properties have been developed, clinically applicable rapamycin analogues are limited to only a few cancers. Akt is an important kinase for cancer cell survival, and mTORC2 can directly phosphorylate Akt.
  • Compound 1 the chemical name is 1-((1s,4s)-4-hydroxycyclohexyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridine-3 -yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one, a dual inhibitor of protein kinase PI3K/mTOR, having the structure shown by:
  • the present invention provides a crystal of a pharmaceutically acceptable salt (e.g., hydrochloride) of Compound 1 of the following formula: or a hydrate thereof:
  • a pharmaceutically acceptable salt e.g., hydrochloride
  • the compound 1 is named 1-((1s,4s)-4-hydroxycyclohexyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridine-3- -1H-imidazo[4,5-c]quinoline-2(3H)-one.
  • the preparation method of the compound 1 and its hydrochloride is described, for example, in Example 18 of WO2015074516A1.
  • the entire disclosure of the WO 2015074516 A1 is incorporated herein by reference.
  • the present invention provides Form I of Compound 1 hydrochloride salt monohydrate, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation may include: 9.08 ⁇ 0.2, 11.196 ⁇ 0.2, 17.393 ⁇ 0.2, 22.504 ⁇ 0.2.
  • the crystal form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) may include: 9.08 ⁇ 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.
  • the crystal form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) includes: 9.08 ⁇ 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.
  • the crystal form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) includes: 9.08 ⁇ 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.
  • Form I has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method A of the crystalline form I of the compound 1 hydrochloride salt monohydrate, comprising:
  • step 1) water may be heated before or after the addition of the compound 1 hydrochloride to dissolve the compound 1 hydrochloride; wherein the amount of water may be from 2 to 80 times the weight of the compound 1 hydrochloride, for example 4 ⁇ 70 times, 6 to 60 times, 8 to 50 times or 10 to 25 times; water can be heated to, for example, 70-100 ° C, such as 75 ° C, 80 ° C, 85 ° C, 90 ° C or 95 ° C;
  • step 2) sodium chloride may be added at a temperature at which the solution of step 1) is maintained; as an example, the amount of sodium chloride may be controlled so as to be 0.1 to 26%, for example, 0.5 to 20, based on the total weight of the solution. %, 0.8 to 15% or 1 to 10%, for example, 3 to 5%;
  • the sodium chloride may be in a suitable form, for example, a sodium chloride solution or a sodium chloride solid may be used.
  • sodium chloride is added and stirred to dissolve;
  • the sodium chloride solution is preferably an aqueous solution of sodium chloride, wherein the weight percentage of sodium chloride may be 10% to a saturated concentration, for example, 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%, 26%;
  • step 3 it can be slowly cooled to below 60 ° C (such as 20 ⁇ 50 ° C) under stirring, crystallization, suction filtration, rinsing, vacuum drying at 15 ⁇ 35 ° C (for example, 20 ° C, 25 ° C, 30 ° C), Form I of Compound 1 hydrochloride salt monohydrate.
  • the invention also provides a preparation method B of the crystalline form I of the compound 1 hydrochloride salt monohydrate, comprising:
  • the aqueous ethanol solution may be heated before or after the addition of the compound 1 hydrochloride to dissolve the compound 1 hydrochloride; wherein the aqueous ethanol solution may be used in an amount of 5 to 80 times the weight of the compound 1 hydrochloride. For example, 10 to 70 times, 20 to 60 times or 30 to 50 times; the aqueous ethanol solution can be heated to, for example, 50 to 100 ° C, such as 55 ° C, 60 ° C, 65 ° C, 70 ° C, 75 ° C, 80 ° C, 85 ° C, 90 ° C or 95 ° C;
  • the mass percentage of ethanol in the aqueous ethanol solution may be, for example, 30 to 99%, such as 40 to 98%, 45 to 95%, 46 to 85%, 48 to 80%, 50 to 75%, or 60 to 70%;
  • step 2) it can be slowly cooled to below 40 ° C (such as 20 ⁇ 30 ° C) under stirring, and subjected to crystallization, suction filtration, and vacuum drying at 15 to 35 ° C (for example, room temperature 25 ° C) to obtain Compound 1 hydrochloride monohydrate.
  • step 2) it can be slowly cooled to below 40 ° C (such as 20 ⁇ 30 ° C) under stirring, and subjected to crystallization, suction filtration, and vacuum drying at 15 to 35 ° C (for example, room temperature 25 ° C) to obtain Compound 1 hydrochloride monohydrate.
  • the present invention also provides the crystalline form II of the compound 1 hydrochloride salt monohydrate, characterized in that the X-ray powder diffraction characteristic peak expressed by the 2 ⁇ angle (°) using Cu-K ⁇ radiation may include: 8.934 ⁇ 0.2, 11.126 ⁇ 0.2, 15.367 ⁇ 0.2, 22.437 ⁇ 0.2.
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction characteristic peaks expressed by 2 ⁇ angle (°) include: 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.
  • the crystal form II uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) includes: 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.
  • Form II has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the crystalline form II of the compound 1 hydrochloride salt monohydrate, comprising:
  • step 2) The mixture of step 1) is allowed to evaporate the solvent to obtain Form II.
  • the two saturated solutions may be mixed at a temperature of 10 to 35 ° C, preferably 20 to 25 ° C;
  • the solvent is selected from an organic solvent, for example, one or more selected from the group consisting of esters.
  • Solvents such as ethyl acetate, methyl acetate, ethyl formate, methyl formate
  • ketone solvents such as acetone, 2-butanone
  • ether solvents such as tetrahydrofuran, 1,4-dioxane, A a base of tert-butyl ether, methyl isopropyl ether, methyl ethyl ether, diethyl ether
  • a nitrile solvent such as acetonitrile, propionitrile
  • the ratio of the total volume of the two saturated solutions is 2 :1 to 1:2, for example 1:1; for example, two saturated solutions can be mixed in a 96-well plate;
  • step 2) the mixture of step 1) can be placed in an atmosphere to slowly evaporate the solvent; as an example, the 96-well plate can be covered with a sealing film that has been pierced through the hole, placed in a fume hood, and naturally dried in an atmosphere. , Form II is obtained.
  • the present invention also provides Form III of Compound 1 hydrochloride, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation 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.
  • the X-ray powder diffraction characteristic peak of the crystal form III expressed by 2 ⁇ angle (°) may 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.
  • Form III has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of Compound 1 hydrochloride salt crystal form III, comprising:
  • step 2) The mixture of step 1) is allowed to evaporate the solvent to obtain crystal form III.
  • the two saturated solutions may be mixed at 35 ° C or lower, preferably 20 to 25 ° C;
  • the solvent is selected from an organic solvent, for example, one or more selected from the group consisting of alcohol solvents (eg, Methanol, ethanol, n-propanol, isopropanol, n-butanol), ether solvents (eg tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methyl isopropyl ether, methyl ethyl)
  • the ratio of the total volume of the two saturated solutions is from 2:1 to 1:2, for example 1:1; for example, two saturated solutions can be mixed in a 96-well plate;
  • step 2) the mixture of step 1) can be placed in an atmosphere to slowly evaporate the solvent; as an example, the 96-well plate can be covered with a sealing film that has been pierced through the hole, placed in a fume hood, and naturally dried in an atmosphere. , Form III is obtained.
  • the present invention also provides Form IV of Compound 1 hydrochloride, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation 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.
  • the crystal form IV uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) may include: 6.178 ⁇ 0.2, 6.614 ⁇ 0.2, 7.181 ⁇ 0.2, 7.470 ⁇ 0.2, 8.996.
  • Form IV has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the crystalline form IV of the compound 1 hydrochloride, comprising:
  • step 2) The mixture of step 1) is allowed to evaporate the solvent to obtain Form IV.
  • the two saturated solutions may be mixed at 35 ° C or lower, preferably 20 to 25 ° C;
  • the solvent is selected from an organic solvent, for example, one or more selected from the group consisting of aromatic hydrocarbon solvents (eg, Benzene, toluene, xylene, chlorobenzene), ester solvent (such as ethyl acetate, methyl acetate, ethyl formate, methyl formate); preferably, the two
  • the ratio of the total volume of each of the saturated solutions is 2:1 to 1:2, for example 1:1; for example, two saturated solutions can be mixed in a 96-well plate;
  • step 2) the mixture of step 1) can be placed in an atmosphere to slowly evaporate the solvent; as an example, the 96-well plate can be covered with a sealing film that has been pierced through the hole, placed in a fume hood, and naturally dried in an atmosphere. , Form IV is obtained.
  • the present invention also provides a crystalline form V of the compound 1 hydrochloride salt dihydrate, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation may include: 6.181 ⁇ 0.2, 8.318 ⁇ 0.2, 18.223 ⁇ 0.2, 31.778 ⁇ 0.2.
  • the crystal form V uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) 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.
  • Form V has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the crystalline form V of the compound 1 hydrochloride salt dihydrate, comprising:
  • step 2) The solution of the step 1) is placed, devitrified, and suction filtered to obtain a crystal form V.
  • the saturated solution of the salt of the compound 1 hydrochloride is a sodium chloride water saturated solution of the compound 1 hydrochloride; the saturated solution may have a sodium chloride content of 1% by weight to a saturated concentration. , for example, 1%, 5%, 10%, 12%, 15%, 16%, 17%, 18%, 20%, 22%, 24%, 25%, 26%;
  • the saturated solution of step 1) is derived from the mother liquor after the filtration of step 3) of the above Form I preparation method A;
  • the solution may be placed below 40 ° C, for example below 30 ° C, such as 20 ⁇ 25 ° C for more than 8 h, for example, placed overnight, or placed for more than 24 h, such as 36 h or more, 48 h or more or more than seven days.
  • the present invention also provides a crystalline form VI of the compound 1 hydrochloride salt dihydrate, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation 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.
  • the crystal form VI uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) 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.
  • Form VI has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the crystalline form VI of the compound 1 hydrochloride salt dihydrate, comprising:
  • the compound 1 hydrochloride can be dissolved in a mixture of water and acetonitrile at 40 ° C or lower, for example, 30 ° C or lower, such as 20 to 25 ° C;
  • the volume percentage of acetonitrile in the mixture of water and acetonitrile can be For example, 5 to 99%, such as 10 to 95%, 15 to 75%, 20 to 60%, or 25 to 50%;
  • a large amount of white crystals may be precipitated by stirring at 40 ° C or lower, for example, 30 ° C or lower, for example, 20 to 25 ° C for 20 hours, and suction-filtered, and the obtained solid is dried under vacuum at 25 ° C to obtain a crystal form VI.
  • the present invention also provides Form VII of Compound 1 hydrochloride salt dihydrate, characterized in that the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation 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.
  • the Form VII uses Cu-K ⁇ radiation
  • the X-ray powder diffraction characteristic peak expressed by 2 ⁇ angle (°) 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.
  • Form VII has a Cu-K ⁇ radiation X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method A of the crystalline form VII of the compound 1 hydrochloride salt dihydrate, comprising:
  • step 1) water is used in an amount of 10 to 500 times, for example 20 to 200 times, such as 60 or 180 times the weight of the compound 1 hydrochloride; preferably, the water is heated before or after the addition of the compound 1 hydrochloride; Preferably, further comprising the step of hot filtration to remove insoluble matter; the water may be heated to, for example, 70-100 ° C, such as 75 ° C, 80 ° C, 85 ° C, 90 ° C or 95 ° C;
  • step 2a the aqueous solution of step 1) is cooled to below 40 ° C, for example below 30 ° C, such as 20 ⁇ 25 ° C crystallization;
  • the crystallization is carried out at 40 ° C or lower, for example, 30 ° C or lower, such as 20 to 25 ° C;
  • the sodium chloride may be in a suitable form, for example, a sodium chloride solution or a sodium chloride solid may be used.
  • sodium chloride is added and stirred to dissolve; for example, sodium chloride may be used in an amount of from 1 to 15 times, for example from 4 to 8 times, of the compound 1 hydrochloride;
  • the filtration may be suction filtration, and the drying may be vacuum drying.
  • the invention also provides a preparation method B of the crystalline form VII of the compound 1 hydrochloride salt dihydrate, comprising:
  • Form VII One or more of the above Forms I-VI were mixed and beaten with water for 3 days to obtain Form VII.
  • the mixed-slurry beating is carried out below 40 ° C, for example, below 30 ° C, such as 20 to 25 ° C; the amount of water used in the mixing and beating is 20 to 200 times the total weight of the crystalline form I-VI, for example 100 times.
  • the invention also provides a pharmaceutical composition comprising one or more of the above crystals or crystal forms.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is preferably a carrier which is relatively non-toxic and harmless to the patient at a concentration consistent with the effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the active ingredient.
  • the pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof is preferably an amount that produces a result or affects the particular condition being treated.
  • the compounds of the present invention can be administered, together with pharmaceutically acceptable carriers well known in the art, in any effective conventional dosage unit form, including immediate release, sustained release and time release formulations, in the following manner: oral, parenteral , local, nasal, ocular, sublingual, rectal, vaginal administration, etc.
  • the compound or a pharmaceutically acceptable salt thereof can be formulated into a solid or liquid preparation such as a capsule, a pill, a tablet, a troche, a lozenge, a melt adhesive. (melt), powder, solution, suspension or emulsion, and can be prepared according to methods known in the art for preparing pharmaceutical compositions.
  • the solid unit dosage form can be a capsule which may be a conventional hard or soft capsule type including, for example, a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof can be compressed into a tablet together with a conventional tablet base (eg, lactose, sucrose, and corn starch) and in combination with: a binder (for example, gum arabic, corn starch or gelatin), a disintegrant for decomposing and dissolving the tablet after administration (for example, potato starch, alginic acid, corn starch and guar gum, gum tragacanth, gum arabic), A lubricant (such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate) for improving the fluidity of tablet granulation and preventing the tablet material from adhering to the surface of the tablet mold and punch ), dyes, colorants, and flavoring agents (such as peppermint, wintergreen or cherry flavor) used to improve the sensory properties of the tablets and make them more acceptable to the patient.
  • a binder for example, gum arabic, corn starch or gelatin
  • Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol) with or without the addition of a pharmaceutically acceptable surface
  • dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol) with or without the addition of a pharmaceutically acceptable surface
  • An active agent, suspending agent or emulsifier may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both.
  • the compound of the present invention can also be administered parenterally as an injection of the compound, i.e., subcutaneously, intravenously, intraocularly, intrasynovally, intramuscularly or intraperitoneally, preferably in the presence of a pharmaceutically acceptable drug carrier.
  • the pharmaceutical carrier can be a sterile liquid or a mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, such as ethanol, isopropanol or cetyl alcohol, a diol such as propylene glycol or polyethylene glycol, a glycerol ketal such as 2,2-dimethyl-1,1-dioxolan-4-methanol, an ether such as polyethylene glycol 400 (PEG400), Oil, fatty acid, fatty acid ester or fatty acid glyceride or acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as soap or detergent, suspending agent, such as glue, card Bom, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants.
  • a pharmaceutically acceptable surfactant such as soap or detergent
  • suspending agent such as glue, card Bom, methylcellulose,
  • Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide and a hydrophobic matrix,
  • the hydrophobic matrix is formed by the condensation of propylene oxide and propylene glycol.
  • composition of the present invention can also be administered in the form of a suppository for rectal administration of a drug.
  • a suppository for rectal administration of a drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and thus can be dissolved in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and thus can be dissolved in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.
  • the pharmaceutical composition may be required or must be delivered to the patient by a mechanical delivery device.
  • a mechanical delivery device for delivering medicaments are well known in the art.
  • direct techniques for administering drugs directly to the brain typically involve placing a drug delivery catheter into the patient's ventricular system to bypass the blood brain barrier.
  • the compounds of the invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse reactions.
  • the invention also relates to such combinations.
  • a compound of the invention can be combined with known chemotherapeutic or anticancer agents (e.g., agents against hyperproliferative diseases or other indications, and the like, and mixtures and combinations thereof).
  • Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-embedded antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors , biological response modifiers or anti-hormones.
  • the invention also provides one or more of the crystalline forms for use in treating or preventing a disease associated with protein kinase activity.
  • the invention also provides a method of modulating (as follows) protein kinase activity comprising contacting the protein kinase with an effective amount of one or more of the above crystalline forms.
  • This method can be used in vivo as well as in vitro.
  • the protein kinase is selected from at least one of mTOR and PI3K.
  • the present application provides a method of treating a disease associated with protein kinase activity, the method comprising administering an effective amount of one or more of the above crystalline forms to an individual in need thereof .
  • the individual can be a mammal, such as a human.
  • the diseases associated with protein kinase activity described in the present specification may be tumors such as leukemia, malignant lymphoma, multiple myeloma, stomach. Intestinal stromal tumor, colon cancer, rectal cancer, breast cancer, liver cancer, stomach cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, choriocarcinoma, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, nerve Glioblastoma, mast cell tumor, brain tumor, germ cell tumor, melanoma, sarcoma, including dermatofibrosarcoma, osteosarcoma.
  • the diseases associated with protein kinase activity described in the present application may also be metabolic diseases (such as diabetes, obesity) and cardiovascular diseases (such as atherosclerosis).
  • the invention also provides the use of one or more of the crystalline forms for the manufacture of a medicament for treating or preventing a disease or condition, which may be a disease or condition associated with protein kinase activity, for example including A disease that inhibits one or both of the kinases of mTOR and PI3K for treatment or prevention.
  • a disease or condition which may be a disease or condition associated with protein kinase activity, for example including A disease that inhibits one or both of the kinases of mTOR and PI3K for treatment or prevention.
  • the invention also provides the use of one or more of the crystalline forms for the manufacture of a medicament for inhibiting one or both of mTOR and PI3K kinase.
  • the disease includes diseases caused by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, or with uncontrolled cell growth, proliferation and/or survival.
  • a disease in which an inappropriate cellular immune response or an inappropriate cellular inflammatory response in particular, the disease is, for example, a hematological tumor, a solid tumor, and/or a metastasis thereof, such as leukemia and myelodysplastic syndrome, malignant lymphoma, Head and neck tumors including brain tumors and brain metastases, chest tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors, and other gynecological tumors, including kidneys Urinary tumors, skin tumors and sarcomas, and/or their metastases, including tumors, bladder tumors, and prostate tumors.
  • the invention also provides the use of a compound of the invention and a composition thereof for the manufacture of a medicament for the treatment of a hyperproliferative disorder in a mammal.
  • Compounds can be utilized to inhibit, block, reduce, reduce, etc. cell proliferation and/or cell division and/or cause apoptosis.
  • Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, benign prostatic hyperplasia (BpH), solid tumors such as breast cancer, respiratory cancer, lung cancer, brain cancer, genital cancer, digestive tract cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases.
  • the condition also includes lymphoma, sarcoma and leukemia.
  • metabolic disease refers to diseases caused by metabolic problems, including metabolic disorders and metabolic extensibility, and mainly includes the following diseases: diabetes, diabetic ketoacidosis, hyperglycemia, hyperosmolar syndrome, hypoglycemia Gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis, etc.
  • cardiovascular disease also known as circulatory system disease
  • the circulatory system refers to the organs and tissues that transport blood in the human body, including the heart and blood vessels (arteries, veins, microvessels). Subdivided into acute and chronic, generally associated with arteriosclerosis. Cardiovascular diseases include: heart disease, hypotension, hypertension, hyperglycemia, stroke, myocardial infarction, thrombosis, arteriosclerosis, etc.
  • the pharmaceutical composition may be an oral tablet, a capsule, a pill, a powder, a sustained release preparation, a solution and a suspension, a sterile solution, suspension or emulsion for parenteral injection.
  • the pharmaceutical composition is suitable for single administration The precise dosage unit dosage form.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day.
  • the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day.
  • a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day.
  • the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
  • the pharmaceutical composition further comprises at least one therapeutic agent (ie, formulated into a dosage form).
  • the pharmaceutical composition and the at least one therapeutic agent are each combined in a separate dosage form into a combined product, such as a kit of parts.
  • the crystal form provided by the invention has good stability, including good stability under three extreme conditions of high temperature, high humidity and strong light, and also maintains good stability during tableting.
  • the crystal form provided by the invention has good in vivo absorption and metabolism properties, including blood concentration, drug time curve AUC, half life and the like. Moreover, the dissolution rate of the crystalline form of the present invention is improved, which is advantageous for application on a formulation.
  • the terms "subject,” “patient,” or “individual” refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or to one or more of the conditions in which the disease occurs, even if a diagnosis of the disease has not yet been made.
  • the symptomatic patient is administered the composition.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton , those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • Figure 1 is an X-ray powder diffraction (XRPD) spectrum of Form I using Cu-K ⁇ radiation in Example I-1.
  • FIG. 3 is a differential scanning calorimetry (DSC) spectrum of Form I in Example I-1.
  • Example I-4 is an XRPD spectrum of a solid of Form I at 60 ° C in Example I-4.
  • Figure 5 is an XRPD spectrum of the solid of Form I in Example I-4 at 25 ° C / 90% RH.
  • Figure 6 is an XRPD spectrum of the solid of Form I under illumination conditions in Example I-4.
  • Figure 7 is a comparison of XRPD before and after the Form I tablet in Example I-5.
  • Figure 8 is an XRPD spectrum of Form II in Example II-1.
  • Figure 9 is a TGA spectrum of Form II in Example II-1.
  • Figure 10 is an XRPD spectrum of Form III in Example III-1.
  • Figure 11 is an XRPD spectrum of Form IV in Example IV-1.
  • Figure 12 is a TGA spectrum of Form IV in Example IV-1.
  • Figure 13 is an XRPD spectrum of Form V in Example V-1.
  • Figure 14 is a TGA spectrum of Form V in Example V-1.
  • Figure 15 is an XRPD spectrum of Form VI in Example VI-1.
  • Figure 16 is a TGA spectrum of Form VI in Example VI-1.
  • Figure 17 is an XRPD spectrum of Form VII in Example VII-1.
  • Figure 18 is a TGA spectrum of Form VII in Example VII-1.
  • Figure 19 is a differential scanning calorimetry (DSC) spectrum of Form VII in Example VII-1.
  • the X-ray powder diffraction in the following examples was determined by a Bruker D8 advance type X-ray powder diffractometer equipped with a LynxEye detector.
  • the 2 ⁇ scan angle of the sample was from 3° to 40°, the scan step was 0.02°, and the tube voltage and tube current were 40KV and 40mA, respectively.
  • the sample tray used for sample measurement is a zero background sample tray.
  • the differential scanning calorimetry (DSC) analysis in the following examples was carried out using TA DSC Q200, the standard sample used for calibration was indium.
  • the 2-3 mg sample was accurately weighed and placed in a TA DSC sample pan and the exact mass of the sample was recorded.
  • the sample was heated to a temperature of 200-250 ° C at a heating rate of 10 ° C/min in a nitrogen flow of 50 mL/min.
  • the thermogravimetric analysis in the following examples was carried out using TA TGA Q500.
  • the 2-3 mg sample was placed in a balanced aluminum sample pan and the sample mass was automatically weighed in a TGA oven.
  • the sample was heated to 200-300 ° C at a rate of 10 ° C/min.
  • the nitrogen flow rates of the nitrogen to the balance chamber and the sample chamber were 40 mL/min and 60 mL/min, respectively.
  • the starting materials, substrates or reagents in the following examples are commercially available (for example, anhydrous ethanol used is commercially available analytically pure ethanol), which is also known in the art. The method was prepared.
  • a small amount of the crystalline form I of the hydrochloride salt of the compound 1 in Example 1 was manually pressed into a tablet having a diameter of 8 mm, and then the tablet was gently crushed, the powder was subjected to XRPD analysis, and the result was XRPD before tableting.
  • the results were compared, if shown in Figure 7, to investigate whether the tableting process had an effect on the crystal form.
  • the XRPD patterns of the powders before and after the tableting of the crystal form I were compared. The results showed that the tableting process did not change the crystal form I, and the XRPD patterns of the powders before and after the tableting were the same.
  • Example I-1 The mother liquid of Example I-1 was allowed to stand at 20 to 25 ° C for a long time for 48 hours or more, white crystals were precipitated, and suction-filtered to obtain crystals, which were tested to be Form V of Compound 1 hydrochloride salt dihydrate.
  • Example I-2 The mother liquid of Example I-2 was allowed to stand at a temperature of 20 to 25 ° C for a long time to precipitate a white crystal, which was filtered under suction to give crystals which were tested to be crystal form V of Compound 1 hydrochloride salt dihydrate.
  • Form I was taken, 10 mg, and 1 ml of water was added thereto, and the mixture was beaten and beaten at 20 to 25 ° C for 3 days to obtain white crystals.
  • Form VII of Compound 1 hydrochloride salt dihydrate was tested.
  • Example VII-3 except that Form I was replaced with one of the above Forms II, III, IV, V, VI, Form VII was obtained.
  • Form VII is completely dissolved in 10 seconds
  • Form I is substantially dissolved in 2 hours, and completely dissolved in 5 hours;
  • Form VI did not dissolve after 5 hours.
  • Form VII is an instant crystalline form and has a good application value in the production of a fast solvent type.

Abstract

本发明涉及咪唑酮类化合物的晶型、其制备方法、药物组合物和用途，属于药物化合物晶体领域。本发明提供的晶型具有良好的稳定性，包括在高温、高湿和强光照等三种极端条件下具有良好的稳定性，并且在压片过程中也保持良好的稳定性。本发明提供的晶型具有良好的体内吸收代谢性质，包括血药浓度、药时曲线AUC、半衰期等。而且，本发明的晶型溶解速度得到改善，有利于制剂上的应用。

Description

咪唑酮类化合物的晶型、其制备方法、药物组合物和用途 技术领域
本发明涉及具有PI3K/mTOR双重抑制活性的咪唑酮类化合物的晶型、其制备方法、药物组合物和用途，属于药物化合物晶体领域。
背景技术：
哺乳动物雷帕霉素靶蛋白(mTOR)是一种非典型丝氨酸/苏氨酸蛋白激酶，属于磷脂酰肌醇-3激酶(phosphoinositide3-kinase，PI3K)相关激酶家族成员，是细胞内合成和分解代谢等细胞功能的主要信号传递分子。mTOR信号通路与营养、能量状态和生长因子有着密切的关系。它调节包括自体吞噬、蛋白、脂类、溶酶体合成和能量代谢、细胞骨架组建、细胞存活等多个细胞过程。在哺乳动物细胞外周营养条件不断变化下，mTOR调控着合成和降解代谢的转换，从而使得细胞在不同的营养条件下能够生长和存活。由于mTOR在细胞中的重要作用，异常或失调的mTOR信号传递能导致人类疾病的发生(例如癌症等疾病)。因此mTOR信号通路逐渐成为设计抗癌药物的一个重要靶点。
PI3K/Akt/mTOR信号通路活化与多种肿瘤发生密切相关，在脑胶质瘤、乳腺癌、卵巢癌中mTOR能够加速细胞周期，减少细胞凋亡，并促进肿瘤细胞的迁移。mTOR的活化起始于一些被配体激活的细胞表面上的生长因子受体，例如表皮生长因子受体和类胰岛素生长因子-1和-2(IGF-1和-2)。受体的激活导致PI3K激酶的激活，从而导致下游效应Akt蛋白的激活。Akt是一个能在多层次上调控细胞存活的调控因子。Akt磷酸化后抑制下游TSC1/2复合物，从而导致mTOR被Rheb所激活。在PI3K/Akt及PEN/Akt和Ras/Erk1/2的信号通路的下游，TSC1/2复合物为调节mTOR的激活起着关键性的作用。
现已发现细胞内存在两种不同的mTOR蛋白质复合体，mTORC1和mTORC2。这两种蛋白质复合体包含独特的与mTOR相互作用的蛋白质，而且各自受不同的机制调控。mTOR抑制剂药物的研发已取得重大进展。雷帕霉素是第一个被发现的mTOR抑制剂，在多种癌症模型中表现出较好的抑癌效果。虽然具有更好药理学特性的雷帕霉素类似物已被开发出来，然而，临床上能应用的雷帕霉素类似物却仅局限在少数几种癌症上。Akt是癌细胞存活的一个重要激酶，而mTORC2可直接磷酸化Akt，这一重要发现为mTORC2在抗癌方面的研究提供了新的思路，同时也促进了同时作用于mTORC1和mTORC2两个靶点的第二代抗癌药物的研发。在癌细胞中同时抑制两个mTOR复合体(mTORC1和mTORC2)的活性有更广泛和更有效的抗癌作用。
化合物1，化学名为1-((1s,4s)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮，为蛋白激酶PI3K/mTOR双重抑制剂，具有下式所示的结构：
Figure PCTCN2016072179-appb-000001
化合物1及其药学上可接受的盐已公开于WO 2015074516A1，据报道，其在细胞和动物模型中显示出了良好的药物活性。为此，开发更稳定、更适于制剂以及吸收代谢较好的化合物1的晶型对其临床应用具有重要意义。
发明内容
本发明提供下式所示化合物1的可药用盐(如盐酸盐)或其水合物的晶体：
Figure PCTCN2016072179-appb-000002
化合物1的命名为1-((1s,4s)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮。所述化合物1及其盐酸盐的制备方法记载于例如WO2015074516A1实施例18。所述WO2015074516A1公开文本的全部内容以引用的方式并入本文。
本发明提供化合物1盐酸盐一水合物的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：9.028±0.2、11.196±0.2、17.393±0.2、22.504±0.2。
根据本发明，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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。
更优选地，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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。
优选地，晶型I具有基本上如图1所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐一水合物的晶型I的制备方法A，包括：
1)将化合物1盐酸盐溶于水中；
2)向步骤1)的溶液中加入氯化钠；
3)降温，析晶，过滤，干燥，得到晶型I。
根据本发明，优选地，
步骤1)中，可以在加入化合物1盐酸盐之前或之后将水加热，以使化合物1盐酸盐溶解；其中，水的用量可以为化合物1盐酸盐重量的2～80倍，例如4～70倍、6～60倍、8～50倍或10～25倍；可将水加热至例如70-100℃，如75℃、80℃、85℃、90℃或95℃；
步骤2)中，可以在保持步骤1)溶液的温度下，加入氯化钠；作为实例，可以控制所述氯化钠的用量以使其占溶液总重量的0.1～26％，例如0.5～20％、0.8～15％或1～10％，例如3～5％；
所述氯化钠可以为其合适的形式，例如可以使用氯化钠溶液或氯化钠固体。优选地，加入氯化钠后搅拌使其溶解；所述氯化钠溶液优选为氯化钠水溶液，其中氯化钠的重量百分含量可以为10％至饱和浓度，例如12％、15％、16％、17％、18％、20％、22％、24％、25％、26％；
步骤3)中，可以在搅拌下缓慢降温至60℃以下(如20～50℃)析晶，抽滤，淋洗，15～35℃(例如20℃、25℃、30℃)真空干燥，得到化合物1盐酸盐一水合物的晶型I。
本发明还提供化合物1盐酸盐一水合物的晶型I的制备方法B，包括：
1)将化合物1盐酸盐溶于乙醇水溶液中；
2)降温，析晶，过滤，干燥，得到晶型I。
根据本发明，优选地，
步骤1)中，可以在加入化合物1盐酸盐之前或之后将乙醇水溶液加热，以使化合物1盐酸盐溶解；其中，乙醇水溶液的用量可以为化合物1盐酸盐重量的5～80倍，例如10～70倍、20～60倍或30～50倍；可将乙醇水溶液加热至例如50-100℃，如55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃或95℃；
乙醇水溶液中乙醇的质量百分比可以为例如30～99％，如40～98％、45～95％、46～85％、48～80％、50～75％或60～70％；
步骤2)中，可以在搅拌下缓慢降温至40℃以下(如20～30℃)析晶，抽滤，15～35℃(例如室温25℃)真空干燥，得到化合物1盐酸盐一水合物的晶型I。
本发明还提供化合物1盐酸盐一水合物的晶型II，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：8.934±0.2、11.126±0.2、15.367±0.2、22.437±0.2。
根据本发明，所述晶型II使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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。
优选地，所述晶型II使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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。
优选地，晶型II具有基本上如图8所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐一水合物的晶型II的制备方法，包括：
1)将化合物1盐酸盐在两种不同溶剂中的饱和溶液混合；
2)使步骤1)的混合物挥发溶剂，得到晶型II。
根据本发明的制备方法，优选地，
步骤1)中，可以在10～35℃，优选20～25℃的温度下，将两种饱和溶液混合；所述溶剂选自有机溶剂，例如选自下列中的一种或多种：酯类溶剂(如乙酸乙酯、乙酸甲酯、甲酸乙酯、甲酸甲酯)、酮类溶剂(如丙酮、2-丁酮)、醚类溶剂(如四氢呋喃、1,4-二氧六环、甲基叔丁基醚、甲基异丙基醚、甲基乙基醚、***)、腈类溶剂(如乙腈、丙腈)；优选地，所述两种饱和溶液各自的总体积之比为2:1～1:2，例如1:1；例如，可将两种饱和溶液在96孔板内混合；
步骤2)中，可以将步骤1)的混合物置于大气环境下缓慢挥发溶剂；作为实例，可通过用扎过洞的封口膜覆盖96孔板，置于通风橱中，大气环境下自然挥干，得到晶型II。
本发明还提供化合物1盐酸盐的晶型III，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
根据本发明，所述晶型III以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，晶型III具有基本上如图10所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐晶型III的制备方法，包括：
1)将化合物1盐酸盐在两种不同溶剂中的饱和溶液混合；
2)使步骤1)的混合物挥发溶剂，得到晶型III。
根据本发明的制备方法，优选地，
步骤1)中，可以在35℃以下，优选20～25℃下，将两种饱和溶液混合；所述溶剂选自有机溶剂，例如选自下列中的一种或多种：醇类溶剂(如甲醇、乙醇、正丙醇、异丙醇、正丁醇)、醚类溶剂(如四氢呋喃、1,4-二氧六环、甲基叔丁基醚、甲基异丙基醚、甲基乙基醚、***)；优选地，所述两种饱和溶液各自的总体积之比为2:1～1:2，例如1:1；例如，可将两种饱和溶液在96孔板内混合；
步骤2)中，可以将步骤1)的混合物置于大气环境下缓慢挥发溶剂；作为实例，可通过用扎过洞的封口膜覆盖96孔板，置于通风橱中，大气环境下自然挥干，得到晶型III。
本发明还提供化合物1盐酸盐的晶型IV，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
根据本发明，所述晶型IV使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，晶型IV具有基本上如图11所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐的晶型IV的制备方法，包括：
1)将化合物1盐酸盐在两种不同溶剂中的饱和溶液混合；
2)使步骤1)的混合物挥发溶剂，得到晶型IV。
根据本发明的制备方法，优选地，
步骤1)中，可以在35℃以下，优选20～25℃下，将两种饱和溶液混合；所述溶剂选自有机溶剂，例如选自下列中的一种或多种：芳烃类溶剂(如苯、甲苯、二甲苯、氯苯)、酯类溶剂(如乙酸乙酯、乙酸甲酯、甲酸乙酯、甲酸甲酯)；优选地，所述两 种饱和溶液各自的总体积之比为2:1～1:2，例如1:1；例如，可将两种饱和溶液在96孔板内混合；
步骤2)中，可以将步骤1)的混合物置于大气环境下缓慢挥发溶剂；作为实例，可通过用扎过洞的封口膜覆盖96孔板，置于通风橱中，大气环境下自然挥干，得到晶型IV。
本发明还提供化合物1盐酸盐二水合物的晶型V，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：6.181±0.2、8.318±0.2、18.223±0.2、31.778±0.2。
根据本发明，所述晶型V使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，晶型V具有基本上如图13所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐二水合物的晶型V的制备方法，包括：
1)制备化合物1盐酸盐的盐水饱和溶液；
2)将步骤1)的溶液放置，析晶，抽滤，得到晶型V。
根据本发明的制备方法，优选地，
步骤1)中，所述化合物1盐酸盐的盐水饱和溶液为化合物1盐酸盐的氯化钠水饱和溶液；所述饱和溶液中氯化钠的重量百分含量可以为1％至饱和浓度，例如1％、5％、10％、12％、15％、16％、17％、18％、20％、22％、24％、25％、26％；
优选地，步骤1)的饱和溶液来自于上述晶型I制备方法A步骤3)过滤后的母液；
步骤2)中，所述溶液可以在40℃以下，例如30℃以下，如20～25℃放置8h以上，例如放置过夜，或者放置24h以上，例如36h以上、48h以上或七天以上。
本发明还提供化合物1盐酸盐二水合物的晶型VI，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
根据本发明，所述晶型VI使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，晶型VI具有基本上如图15所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐二水合物的晶型VI的制备方法，包括：
1)将化合物1盐酸盐溶于水和乙腈的混合液中；
2)搅拌，析出晶体，过滤，干燥，得晶型VI。
根据本发明，优选地，
步骤1)中，可以在40℃以下，例如30℃以下，如20～25℃，将化合物1盐酸盐溶于水和乙腈的混合液中；水和乙腈的混合液中乙腈的体积百分比可以为例如5～99％，如10～95％、15～75％、20～60％或25～50％；
步骤2)中，可以在40℃以下，例如30℃以下，如20～25℃，搅拌20小时，析出大量白色晶体，抽滤，所得固体在25℃真空干燥，得到晶型VI。
本发明还提供化合物1盐酸盐二水合物的晶型VII，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：6.264±0.2、6.760±0.2、7.556±0.2、14.455±0.2、20.123±0.2、26.373±0.2。
根据本发明，所述晶型VII使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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。
优选地，晶型VII具有基本上如图17所示的Cu-Kα辐射X-射线粉末衍射图。
本发明还提供化合物1盐酸盐二水合物的晶型VII的制备方法A，包括：
1)将化合物1盐酸盐溶于水中；
2a)将步骤1)的水溶液冷却析晶；或2b)向步骤1)的水溶液中加入氯化钠，搅拌析晶；
3)过滤，干燥，得晶型VII。
根据本发明的方法，优选地，
步骤1)中，水的用量为化合物1盐酸盐重量的10～500倍，例如20～200倍，如60或180倍；优选地，在加入化合物1盐酸盐之前或之后将水加热；优选地，还包括热过滤除去不溶物的步骤；可将水加热至例如70-100℃，如75℃、80℃、85℃、90℃或95℃；
步骤2a)中，将步骤1)的水溶液冷却到40℃以下，例如30℃以下，如20～25℃析晶；
步骤2b)中，在40℃以下，例如30℃以下，如20～25℃搅拌析晶；氯化钠可以为其合适的形式，例如可以使用氯化钠溶液或氯化钠固体。优选地，加入氯化钠后搅拌使其溶解；例如，氯化钠的用量可以为化合物1盐酸盐的1～15倍，例如4～8倍；
其中步骤2a)和2b)为择一进行；
步骤3)中，所述过滤可以为抽滤，所述干燥可以为真空干燥。
本发明还提供化合物1盐酸盐二水合物的晶型VII的制备方法B，包括：
将上述晶型I-VI中的一种或多种，使用水进行混旋打浆3天，得到晶型VII。
优选地，所述方法中混旋打浆在40℃以下，例如30℃以下，如20～25℃下进行；混旋打浆中水的用量为晶型I-VI总重量的20～200倍，例如100倍。
本发明还提供一种药物组合物，包含上述晶体或晶型中的一种或多种。
根据本发明，所述药物组合物还可包含药学上可接受的载体。
药学上可接受的载体优选是这样的载体，其在与活性成分的有效活性一致的浓度下对患者相对无毒且无害，以致于由所述载体引起的任何副作用不会破坏所述活性成分的有益作用。化合物或其药学上可接受的盐的药学有效量优选是对正在治疗的具体病况产生结果或者产生影响的量。可使用包括速释、缓释和定时释放制剂在内的任意有效的常规剂量单位形式，将本发明的化合物与本领域公知的药学上可接受的载体一起以如下方式给药：口服、肠胃外、局部、鼻腔、眼部、舌下、直肠、***给药等。
对于口服给药，可将所述化合物或其药学上可接受的盐配制成固体或液体制剂，例如胶囊剂、丸剂、片剂、含锭剂(troche)、锭剂(lozenge)、熔胶剂(melt)、散剂、溶液剂、混悬剂或乳剂，并且可根据本领域已知的用于制备药物组合物的方法来制备。固体单位剂型可为胶囊剂，其可为普通的硬胶囊型或软胶囊型，包含例如表面活性剂、润滑剂和惰性填充剂(例如乳糖、蔗糖、磷酸钙和玉米淀粉)。
在另一实施方案中，可将本发明的化合物或其药学上可接受的盐和常规片剂基质(例如乳糖、蔗糖和玉米淀粉)一起并与如下物质组合压制成片剂：粘合剂(例如***胶、玉米淀粉或明胶)、用于辅助给药后片剂的分解和溶出的崩解剂(例如土豆淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍树胶、***胶)、用于提高片剂制粒的流动性并且防止片剂材料与片剂模具和冲头的表面粘附的润滑剂(例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌)、染料、着色剂，以及用于改善片剂的感官性质并使它们更容易被患者接受的调味剂(例如薄荷油、冬青油或樱桃香精)。用于口服液体剂型的适合的赋形剂包括磷酸二钙和稀释剂，例如水和醇(例如乙醇、苯甲醇和聚乙烯醇)，所述稀释剂添加或不添加有药学上可接受的表面活性剂、助悬剂或乳化剂。可以存在各种其它物质作为包衣或者用于改变剂量单位的物理形式。例如可用虫胶、糖或二者将片剂、丸剂或胶囊剂包衣。
还可将本发明的化合物以所述化合物的注射剂进行肠胃外给药，即皮下、静脉内、眼内、滑膜内、肌内或腹膜内给药，所述注射剂优选在含有药物载体的生理学可接受的稀释剂中，所述药物载体可为无菌液体或液体的混合物，所述液体为例如水，盐水，葡萄糖水溶液和相关的糖溶液，醇例如乙醇、异丙醇或十六醇，二醇例如丙二醇或聚乙二醇，甘油缩酮例如2,2-二甲基-1,1-二氧戊环-4-甲醇，醚例如聚乙二醇400(PEG400)， 油，脂肪酸，脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯，所述稀释剂添加或不添加有药学上可接受的表面活性剂，例如肥皂或洗涤剂，助悬剂例如果胶、卡波姆、甲基纤维素、羟丙甲纤维素或羧甲基纤维素，或乳化剂和其它药学辅剂。
用于肠胃外制剂的示例性表面活性剂是聚乙烯脱水山梨糖醇脂肪酸酯类，例如脱水山梨糖醇单油酸酯，以及环氧乙烷与疏水性基质的高分子量加合物，所述疏水性基质由环氧丙烷和丙二醇缩合形成。
还可将本发明的组合物以用于药物的直肠给药的栓剂的形式给药。可通过将药物与在常温下为固体但是在直肠温度下为液体并且因此可在直肠中溶化而释放所述药物的适合的无刺激性的赋形剂混合来制备这些组合物。此类物质是例如可可脂和聚乙二醇。
用于肠胃外给药的控释制剂包括本领域已知的脂质体微球、聚合物微球和聚合物凝胶制剂。
可能需要或必须通过机械递送装置将所述药物组合物递送至患者。用于递送药剂的机械递送装置的构造和用途是本领域公知的。例如将药物直接给药至脑的直接技术通常涉及将药物递送导管置入患者的脑室***以绕过血脑屏障。
可将本发明的化合物作为单一药剂给药或者与一种或多种其它药剂组合给药，其中所述组合不会引起不可接受的不良反应。本发明还涉及此类组合。例如，可将本发明的化合物与已知的化疗剂或抗癌剂(例如抗过度增殖性疾病或其它适应症的药剂等)以及与它们的混合物和组合进行组合。其它适应症药剂包括但不限于抗血管生成剂、有丝***抑制剂、烷化剂、抗代谢剂、DNA-嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物应答调节剂或抗激素。
本发明还提供所述晶型中的一种或多种，其用于治疗或预防与蛋白激酶活性相关的疾病。
本发明还提供调节(如下调)蛋白激酶活性的方法，其中包括将所述蛋白激酶与有效量的上述晶型中的一种或多种接触。该方法可以用于体内，也可以用于体外。优选地，所述蛋白激酶选自mTOR和PI3K中至少之一。
根据本申请的另一个方面，本申请提供了一种治疗与蛋白激酶活性相关的疾病的方法，所述方法包括将有效量的上述晶型中的一种或多种施用于有此需求的个体。所述个体可以为哺乳动物，如人类。
本说明书所述的与蛋白激酶活性相关的疾病(例如通过抑制mTOR和PI3K中一种或两种激酶来治疗或预防的疾病)可以为肿瘤，例如白血病、恶性淋巴瘤、多发性骨髓瘤、胃肠道间质瘤、结肠癌、直肠癌、乳腺癌、肝癌、胃癌、卵巢癌、子宫癌、***、***癌、绒毛膜癌、肺癌、肾癌、***癌、膀胱癌、胰腺癌、神经胶母细胞瘤、肥大细胞肿瘤、脑瘤、生殖细胞肿瘤、黑色素瘤、肉瘤，包括隆突性皮肤纤维肉瘤、骨肉瘤。 本申请中所述的与蛋白激酶活性相关的疾病还可以为代谢性疾病(例如糖尿病、肥胖症)和心血管疾病(例如动脉粥样硬化)。
本发明还提供所述晶型中的一种或多种用于制备治疗或预防疾病或病症的药物的用途，所述疾病或病症可以是与蛋白激酶活性相关的疾病或病症，例如包括可通过抑制mTOR和PI3K中一种或两种激酶来治疗或预防的疾病。
本发明还提供所述晶型中的一种或多种用于制备抑制mTOR和PI3K激酶中一种或两种的药物中的用途。
所述疾病包括由不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答引起的疾病，或者伴有不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答的疾病，特别地，所述疾病为例如血液肿瘤、实体瘤和/或它们的转移，如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头部和颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤、包括肾肿瘤、膀胱瘤和***瘤在内的泌尿***肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移。
本发明还提供本发明的化合物及其组合物在制备治疗哺乳动物的过度增殖性病症的药物中的用途。可利用化合物来抑制、阻断、降低、减少等细胞增殖和/或细胞***和/或引起凋亡。过度增殖性病症包括但不限于银屑病、瘢痕疙瘩和其它影响皮肤的增生、良性***增生(BpH)、实体瘤例如乳腺癌、呼吸道癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌以及它们的远端转移。所述病症还包括淋巴瘤、肉瘤和白血病。
本文所用的“代谢性疾病”是指因代谢问题引起的疾病，包括代谢障碍和代谢旺盛等原因，主要包括以下这些疾病：糖尿病、糖尿病酮症酸中毒、高血糖高渗综合征、低血糖症、痛风、蛋白质-能量营养不良症、维生素A缺乏病、坏血病、维生素D缺乏病、骨质疏松症等。
本文所用的“心血管疾病”又称为循环***疾病，是一系列涉及循环***的疾病，循环***指人体内运送血液的器官和组织，主要包括心脏、血管(动脉、静脉、微血管)，可以细分为急性和慢性，一般都是与动脉硬化有关。心血管疾病包括：心脏病、低血压、高血压、高血糖症、中风、心肌梗塞、血栓、动脉硬化等。
这些病症已在人类中得到良好的表征，但是还以相似的病因学存在于其它哺乳动物中，并且可通过给药本发明的药物组合物进行治疗。
在一些实施方式中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液，用于外用的软膏或乳膏，或者用于直肠给药的栓剂。在其它实施方式中，所述药物组合物为适合单次施予 精确剂量的单位剂型。在其它实施方式中，所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。在其它实施方式中，所述化合物的量的范围为约0.5mg/kg体重/天-约50mg/kg体重/天。在一些实施方式中，所述化合物的量为约0.001g/天-约7g/天。在其它实施方式中，所述化合物的量为约0.002g/天-约6g/天。在其它实施方式中，所述化合物的量为约0.005g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.01g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.02g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.05g/天-约2.5g/天。在其它实施方式中，所述化合物的量为约0.1g/天-约1g/天。在其它实施方式中，低于上述范围下限的剂量水平可能已经是足够的。在其它实施方式中，可能需要高于上述范围上限的剂量水平。在一些实施方式中，以单剂量施用所述化合物，每天一次。在其它实施方式中，以多剂量施用所述化合物，每天不只一次。在一些实施方式中，每天施用两次所述化合物。在其它实施方式中，每天施用三次所述化合物。在其它实施方式中，每天施用四次所述化合物。在其它实施方式中，每天施用四次以上的所述化合物。在一些实施方式中，所述药物组合物施用于的个体为哺乳动物。在其它实施方式中，所述哺乳动物是人。在其它实施方式中，所述药物组合物还包含至少一种治疗剂(即制成一种剂型)。在一些实施方式中，所述药物组合物和至少一种治疗剂分别以独立的剂型组合成组合产品，如套装药品(kitofpart)。
本发明提供的晶型具有良好的稳定性，包括在高温、高湿和强光照等三种极端条件下具有良好的稳定性，并且在压片过程中也保持良好的稳定性。本发明提供的晶型具有良好的体内吸收代谢性质，包括血药浓度、药时曲线AUC、半衰期等。而且，本发明的晶型溶解速度得到改善，有利于制剂上的应用。
药学术语
某些药学术语本文所用的有关术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中，所述哺乳动物为人。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，预防其它症状，改善或预防导致症状的潜在代谢原因，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生 理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方式中，本文讨论的化合物和组合物通过口服施用。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
附图说明
图1为实施例I-1中晶型I使用Cu-Kα辐射的X-射线粉末衍射(XRPD)谱图。
图2为实施例I-1中晶型I的热失重分析(TGA)谱图。
图3为实施例I-1中晶型I的差示扫描量热(DSC)谱图。
图4为实施例I-4中晶型I在60℃条件下固体的XRPD谱图。
图5为实施例I-4中晶型I在25℃/90％RH条件下固体的XRPD谱图。
图6为实施例I-4中晶型I在光照条件下固体的XRPD谱图。
图7为实施例I-5中晶型I压片前后的XRPD对比图。
图8为实施例II-1中晶型II的XRPD谱图。
图9为实施例II-1中晶型II的TGA谱图。
图10为实施例III-1中晶型III的XRPD谱图。
图11为实施例IV-1中晶型IV的XRPD谱图。
图12为实施例IV-1中晶型IV的TGA谱图。
图13为实施例V-1中晶型V的XRPD谱图。
图14为实施例V-1中晶型V的TGA谱图。
图15为实施例VI-1中晶型VI的XRPD谱图。
图16为实施例VI-1中晶型VI的TGA谱图。
图17为实施例VII-1中晶型VII的XRPD谱图。
图18为实施例VII-1中晶型VII的TGA谱图。
图19为实施例VII-1中晶型VII的差示扫描量热(DSC)谱图。
具体实施方式
以下通过实施例对本发明的技术方案进行详细说明，以便更好的理解本发明的技术方案和实质。所述实施例仅为示例性的描述，不应当理解为对本发明保护范围的限制。本领域技术人员根据发明内容及以下实施例所作出的变型或改变均涵盖在本发明要求保护的范围内。
以下实施例中X-射线粉末衍射是由Bruker D8 advance型X-射线粉末衍射仪测定的，该仪器配备了LynxEye检测器。样品的2θ扫描角度是从3°到40°，扫描步长是0.02°，管电压和管电流分别为40KV和40mA。样品测量采用的样品盘为零背景样品盘。
以下实施例中的差示扫描量热(DSC)分析使用TA DSC Q200进行，其校正使用的标准样品是铟。2-3mg样品精确称重后置于TA DSC样品盘中，并记录下样品的准确质量。样品在50mL/min的氮气流中以10℃/min的升温速率加热至200-250℃。以下实施例中的热重分析使用TA TGA Q500进行。2-3mg样品置于已平衡的铝制样品盘中，样品质量在TGA加热炉内自动称量。样品以10℃/min的速率加热至200-300℃。测试过程中，氮气对天平室和样品室的氮气流量分别是40mL/min和60mL/min。
除非另有说明，如下实施例中的原料、底物或试剂均为市售可得的商品(例如所用无水乙醇为市售的分析纯无水乙醇)，其也可通过本领域已知的方法制备获得。
实施例I-1晶型I制备
将化合物1盐酸盐96g溶于浴温100℃的860ml水中，趁热加入43g氯化钠固体，搅拌下使其溶解，缓慢降温至30℃析晶，抽滤并用100ml水淋洗，所得固体在25℃真空干燥，得到86g黄绿色结晶，经测试为化合物1盐酸盐一水合物的晶型I。
实施例I-2晶型I制备
将化合物1的盐酸盐110g溶于浴温100℃的2L水中，趁热加入100g氯化钠在500ml水中的溶液，搅拌下缓慢降温至20℃析晶，抽滤并用100ml水淋洗，所的固体在30℃真空干燥，得到97g黄绿色结晶，经测试为化合物1盐酸盐一水合物的晶型I。
实施例I-3晶型I制备
将化合物1的盐酸盐0.5g溶于浴温85℃的10ml乙醇和5.5ml水的混合液中，搅拌下自然冷却至25℃析晶，抽滤，所的固体在25℃真空干燥，得到0.36g黄绿色结晶，经测试为化合物1盐酸盐一水合物的晶型I。
实施例I-4晶型I稳定性实验
取少量实施例I-1中化合物1盐酸盐一水合物的晶型I，分别放入药品稳定性实验箱中，控制表1所列的条件进行稳定性实验，纯度和含量所得结果列于表I-1中，晶型测 试结果如图4到6所示。
如表I-1所示，在高温、高湿和强光照等三种极端条件下，晶型I的化合物纯度和含量均无明显变化(纯度浮动在0.2％以内，含量浮动在1％以内)，证明了晶型I的稳定性较好。
如图4至图6所示，在高温、高湿和强光照等三种极端条件下，晶型I均保持晶型未变，证明了晶型I的稳定性较好。
表I-1晶型I固体稳定性实验结果
Figure PCTCN2016072179-appb-000003
实施例I-5晶型I压片稳定性实验
取少量实施例1中化合物1盐酸盐一水合物的晶型I，手动压成直径为8mm的药片，然后将药片轻轻碾碎，粉末进行XRPD分析，并将结果与压片前的XRPD结果进行对比，如果图7所示，用以考察压片过程否对晶型产生影响。对晶型I压片前后粉末的XRPD图谱进行了对比，结果表明，压片过程对晶型I无改变，压片前后粉末的XRPD图谱相同。
实施例I-6晶型I的SD大鼠口服给药代谢实验
将11.392mg晶型I的化合物1盐酸盐的悬浮于5.274mL 0.5％的羧甲基纤维素钠中，涡旋，形成均一混悬液，之后超声2min最终制成浓度为2mg/mL的均一混悬溶液(给药当天现用现配，存放不超过4小时)。对三只SD大鼠按10mg/kg体重剂量灌胃给药，按设定的时间点取血分析，所得结果列于下表I-2：
表I-2：晶型I大鼠灌胃药物代谢实验数据
Figure PCTCN2016072179-appb-000004
从表I-2可以得知，晶型I的药物给药后，最高血药浓度(Cmax)可达14600ng/ml，AUC last可达190696h*ng/mL，这在药物代谢中是非常高的数值，同时5.5h的半衰期也是药物代谢中比较理想的数值，这些都证明了晶型I的药物在动物体内的吸收代谢性质良好。
实施例II-1晶型II制备
室温下，将化合物1盐酸盐的乙酸乙酯饱和溶液和2-丁酮饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐一水合物的晶型II。
实施例II-2晶型II制备
室温下，将化合物1盐酸盐的四氢呋喃饱和溶液和乙腈饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐一水合物的晶型II。
实施例II-3晶型II制备
室温下，将化合物1盐酸盐的四氢呋喃饱和溶液和丙酮饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐一水合物的晶型II。
实施例III-1晶型III制备
室温下，将化合物1盐酸盐的乙醇饱和溶液和异丙醇饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐的晶型III。
实施例III-2晶型III制备
室温下，将化合物1盐酸盐的异丙醇饱和溶液和甲基叔丁基醚饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐的晶型III。
实施例IV-1晶型IV制备
室温下，将化合物1盐酸盐的甲苯饱和溶液和乙酸异丁酯饱和溶液各100微升，于96孔板内混合，用扎过洞的封口膜覆盖，置于通风橱中，大气环境下自然挥干，得到晶体，经测试为化合物1盐酸盐的晶型IV。
实施例V-1晶型V制备
将实例I-1的母液在20～25℃长时间放置48小时以上，析出白色结晶，抽滤，得到晶体，经测试为化合物1盐酸盐二水合物的晶型V。
实施例V-2晶型V制备
将实例I-2的母液在20～25℃长时间放置，析出白色结晶，抽滤，得到晶体，经测试为化合物1盐酸盐二水合物的晶型V。
实施例VI-1晶型VI制备
将化合物1的盐酸盐0.5g于20～25℃溶于50ml水和20ml乙腈的混合液中，室温搅拌20小时，析出大量白色晶体，抽滤，所得固体在25℃真空干燥，得到0.27g白色结晶，经测试为化合物1盐酸盐二水合物的晶型VI。
实施例VII-1晶型VII制备
将化合物1的盐酸盐0.5g溶于加热至90℃的90ml水，冷却到室温(20～25℃)，搅拌下加入3g氯化钠，室温搅拌20小时，析出大量黄白色固体，抽滤，所得固体在25℃真空干燥，得到0.46g白色结晶，经测试为化合物1盐酸盐二水合物的晶型VII。
实施例VII-2晶型VII制备
将化合物1的盐酸盐0.5g大部分溶于加热至100℃的12ml水，热过滤除掉少量不溶物，母液搅拌下自然冷却到室温(20～25℃)，抽滤，所得固体在25℃真空干燥，得到0.21g白色结晶，经测试为化合物1盐酸盐二水合物的晶型VII。
实施例VII-3晶型VII制备
将上述晶型I，取10mg，加入1ml水，20～25℃混旋打浆3天，得到白色结晶， 经测试为化合物1盐酸盐二水合物的晶型VII。
实施例VII-4晶型VII制备
按照实施例VII-3，但将晶型I替换为上述晶型II、III、IV、V、VI中的一种，均获得晶型VII。
实施例VII-5晶型VII的溶解速度测试
分别称取取化晶型VII、晶型I、晶型VI各3mg，分别放入3个1ml的塑料离心管中，每管加1ml蒸馏水，于20～25℃晃动5秒钟后放置，观察溶解现象：
晶型VII在10秒内全部溶清；
晶型I在2小时内基本溶清，5小时内全部溶清；
晶型VI在5小时后未溶清。
由此可见，晶型VII是速溶晶型，在制作速溶剂型方面有很好的应用价值。

Claims (12)

  1. 下式所示化合物1的可药用盐(如盐酸盐)或其水合物的晶体：
    Figure PCTCN2016072179-appb-100001
  2. 权利要求1所述的晶体，其为化合物1盐酸盐一水合物的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：9.028±0.2、11.196±0.2、17.393±0.2、22.504±0.2；
    例如，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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；
    更优选地，所述晶型I使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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；
    优选地，晶型I具有基本上如图1所示的Cu-Kα辐射X-射线粉末衍射图。
  3. 权利要求1所述的晶体，其为化合物1盐酸盐一水合物的晶型II，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：8.934±0.2、11.126±0.2、15.367±0.2、22.437±0.2；
    优选地，所述晶型II使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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；
    优选地，所述晶型II使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰包括：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；
    优选地，晶型II具有基本上如图8所示的Cu-Kα辐射X-射线粉末衍射图。
  4. 权利要求1所述的晶体，其为化合物1盐酸盐的晶型III，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，所述晶型III以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，晶型III具有基本上如图10所示的Cu-Kα辐射X-射线粉末衍射图。
  5. 权利要求1所述的晶体，其为化合物1盐酸盐的晶型IV，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，所述晶型IV使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，晶型IV具有基本上如图11所示的Cu-Kα辐射X-射线粉末衍射图。
  6. 权利要求1所述的晶体，其为化合物1盐酸盐二水合物的晶型V，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：6.181±0.2、8.318±0.2、18.223±0.2、31.778±0.2；
    根据本发明，所述晶型V使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，晶型V具有基本上如图13所示的Cu-Kα辐射X-射线粉末衍射图。
  7. 权利要求1所述的晶体，其为化合物1盐酸盐二水合物的晶型VI，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    根据本发明，所述晶型VI使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，晶型VI具有基本上如图15所示的Cu-Kα辐射X-射线粉末衍射图。
  8. 权利要求1所述的晶体，其为化合物1盐酸盐二水合物的晶型VII，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：6.264±0.2、6.760±0.2、7.556±0.2、14.455±0.2、20.123±0.2、26.373±0.2；
    根据本发明，所述晶型VII使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射特征峰可以包括：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；
    优选地，晶型VII具有基本上如图17所示的Cu-Kα辐射X-射线粉末衍射图。
  9. 权利要求2所述晶体的制备方法，选自下列制备方法A或制备方法B中的一种：
    制备方法A，包括：
    1)将化合物1盐酸盐溶于水中；
    2)向步骤1)的溶液中加入氯化钠；
    3)降温，析晶，过滤，干燥，得到晶型I；
    优选地，
    步骤1)中，可以在加入化合物1盐酸盐之前或之后将水加热，以使化合物1盐酸盐溶解；其中，水的用量可以为化合物1盐酸盐重量的2～80倍，例如4～70倍、6～60倍、8～50倍或10～25倍；可将水加热至例如70-100℃，如75℃、80℃、85℃、90℃或95℃；
    步骤2)中，可以在保持步骤1)溶液的温度下，加入氯化钠；作为实例，可以控制所述氯化钠的用量以使其占溶液总重量的0.1～26％，例如0.5～20％、0.8～15％或1～10％，例如3～5％；
    所述氯化钠可以为其合适的形式，例如可以使用氯化钠溶液或氯化钠固体。优选地，加入氯化钠后搅拌使其溶解；所述氯化钠溶液优选为氯化钠水溶液，其中氯化钠的重量百分含量可以为10％至饱和浓度，例如12％、15％、16％、17％、18％、20％、22％、24％、25％、26％；
    步骤3)中，可以在搅拌下缓慢降温至60℃以下(如20～50℃)析晶，抽滤，淋洗，15～35℃(例如20℃、25℃、30℃)真空干燥，得到化合物1盐酸盐一水合物的晶型I；
    或者，
    制备方法B，包括：
    1)将化合物1盐酸盐溶于乙醇水溶液中；
    2)降温，析晶，过滤，干燥，得到晶型I；
    优选地，
    步骤1)中，可以在加入化合物1盐酸盐之前或之后将乙醇水溶液加热，以使化合物1盐酸盐溶解；其中，乙醇水溶液的用量可以为化合物1盐酸盐重量的5～80倍，例如10～70倍、20～60倍或30～50倍；可将乙醇水溶液加热至例如50-100℃，如55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃或95℃；
    乙醇水溶液中乙醇的质量百分比可以为例如30～99％，如40～98％、45～95％、46～85％、48～80％、50～75％或60～70％；
    步骤2)中，可以在搅拌下缓慢降温至40℃以下(如20～30℃)析晶，抽滤，15～35℃(例如室温25℃)真空干燥，得到化合物1盐酸盐一水合物的晶型I。
  10. 权利要求8所述晶体的制备方法，选自下列制备方法A或制备方法B中的一种：
    制备方法A，包括：
    1)将化合物1盐酸盐溶于水中；
    2a)将步骤1)的水溶液冷却析晶；或2b)向步骤1)的水溶液中加入氯化钠，搅拌析晶；
    3)过滤，干燥，得晶型VII；
    优选地，
    步骤1)中，水的用量为化合物1盐酸盐重量的10～500倍，例如20～200倍，如60或180倍；优选地，在加入化合物1盐酸盐之前或之后将水加热；优选地，还包括热过滤除去不溶物的步骤；可将水加热至例如70-100℃，如75℃、80℃、85℃、90℃或95℃；
    步骤2a)中，将步骤1)的水溶液冷却到40℃以下，例如30℃以下，如20～25℃析晶；
    步骤2b)中，在40℃以下，例如30℃以下，如20～25℃搅拌析晶；氯化钠可以为其合适的形式，例如可以使用氯化钠溶液或氯化钠固体。优选地，加入氯化钠后搅拌使其溶解；例如，氯化钠的用量可以为化合物1盐酸盐的1～15倍，例如4～8倍；
    步骤3)中，所述过滤可以为抽滤，所述干燥可以为真空干燥；
    或者，
    制备方法B，包括：
    将上述晶型I-VI中的一种或多种，使用水进行混旋打浆3天，得到晶型VII。
    优选地，所述方法中混旋打浆在40℃以下，例如30℃以下，如20～25℃下进行；混旋打浆中水的用量为晶型I-VI总重量的20～200倍，例如100倍。
  11. 药物组合物，包含权利要求1-8任一项所述晶体中的一种或多种。
  12. 权利要求1-8任一项所述晶体用于制备治疗或预防疾病的药物的用途，特别是用于制备抑制mTOR和PI3K激酶中一种或两种的药物中的用途。
PCT/CN2016/072179 2016-01-26 2016-01-26 咪唑酮类化合物的晶型、其制备方法、药物组合物和用途 WO2017128042A1 (zh)

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WO2015074516A1 (zh) 2013-11-20 2015-05-28 北京富龙康泰生物技术有限公司 咪唑酮类衍生物、其药物组合物和用途

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WO2015074516A1 (zh) 2013-11-20 2015-05-28 北京富龙康泰生物技术有限公司 咪唑酮类衍生物、其药物组合物和用途

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GOODMAN; GILMAN: "The Pharmacological Basis of Therapeutics", PERGAMON
REMINGTON: "Pharmaceutical Sciences", MACK PUBLISHING CO.

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