WO2017050111A1 - 5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型及其制备方法 - Google Patents

5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型及其制备方法 Download PDF

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WO2017050111A1
WO2017050111A1 PCT/CN2016/097774 CN2016097774W WO2017050111A1 WO 2017050111 A1 WO2017050111 A1 WO 2017050111A1 CN 2016097774 W CN2016097774 W CN 2016097774W WO 2017050111 A1 WO2017050111 A1 WO 2017050111A1
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crystal form
solvent system
cancer
preparation
present
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French (fr)
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陈敏华
张炎锋
刁小娟
张晓宇
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苏州晶云药物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention relates to the field of chemical medicine, in particular to crystals of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine hydrochloride Type and its preparation method.
  • BKM120 Bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine
  • compound of formula I also known as BKM120 (Buparlisib)
  • BKM120 is New drug for breast cancer developed by Novartis. At present, the drug treatment of metastatic breast cancer is in the phase III clinical and confirmatory I/II clinical stage.
  • BKM120 is a reversible inhibitor of class I phosphoinositide-3 kinase (PI3K). The results show that it has anti-tumor activity against ER-positive breast cancer cell lines and implanted tumors, and can be used alone or in combination with endocrine therapy.
  • PI3K phosphoinositide-3 kinase
  • Patent CN103140479A discloses crystalline forms of the compounds of formula I and crystalline forms thereof. Specifically, the patent discloses the compound hemihydrate and anhydrate of the formula I, the monohydrate form of the compound of the formula I, the monohydrate form Ha, the anhydrate form A, the form B and the solvate form Sa, the form Sb, the form Sc, form Sd, and form Se. From the application point of view, the monohydrate form Ha and the anhydride form A are clearly more preferred crystal forms than the solvate, however, for these two preferred crystal forms, their properties such as stability are not Satisfactory.
  • the inventors of the present application unexpectedly discovered 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl) in the form of a new crystal during the course of the study.
  • 2-pyridylamine hydrochloride, the crystal form and the existing 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridine The amine hydrochloride crystal form has better stability than the crystal form and is very important for drug development.
  • One of the objects of the present invention is to provide a new crystalline form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine hydrochloride. Named as Form H.
  • a second object of the present invention is to provide a process and use for the preparation of the novel Form H.
  • the present invention adopts the following technical solutions:
  • Form H of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine monohydrochloride (hereinafter referred to as the present invention Form H)
  • its X-ray powder diffraction pattern at 25 ° C has characteristic peaks at 2theta values of 16.6 ° ⁇ 0.2 °, 15.8 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form H also has a diffraction peak at one or more of 2theta values of 9.2 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, preferably, Form H
  • the X-ray powder diffraction pattern has diffraction peaks at 2theta values of 9.2 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 °, and 7.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form H has a diffraction peak at one or more of 2theta values of 10.5° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 29.6° ⁇ 0.2°, preferably, Form H X-ray powder
  • the final diffraction pattern has diffraction peaks at 2theta values of 10.5 ° ⁇ 0.2 °, 22.7 ° ⁇ 0.2 °, and 29.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form H at 25 ° C is 16.6 ° ⁇ 0.2 °, 15.8 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 9.2 ° ⁇ 0.2 ° at 2theta.
  • the X-ray powder diffraction pattern of Form H is substantially as shown in FIG.
  • the form H begins to exhibit an endothermic peak near heating at 81 ° C, 160 ° C, and 263 ° C, and an exothermic peak begins to appear near the heating to about 200 ° C
  • the differential scanning calorimetry diagram is substantially as follows. Figure 2 shows.
  • Form H has a weight loss gradient of about 7.4% when heated to 157 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • the crystalline form H of the invention is a hydrate.
  • a second object of the present invention is to provide a process for the preparation of Form H which will be 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-
  • the 2-pyridylamine free base is reacted with hydrochloric acid in a solvent system, and stirred and crystallized at a temperature of -20 ° C to 25 ° C to obtain a crystal form H.
  • the solvent system is a mixed solvent system of a halogenated hydrocarbon and an aromatic hydrocarbon, wherein a mixed solvent system of dichloromethane and toluene is preferred.
  • the volume ratio of dichloromethane to toluene is preferably from 1:3 to 1:1, most preferably 2:3.
  • the solvent system is a mixed solvent system of a halogenated hydrocarbon, an aromatic hydrocarbon and a C1-C6 alcohol, wherein the halogenated hydrocarbon is preferably dichloromethane, the aromatic hydrocarbon is preferably toluene, and the C1-C6 alcohol is preferred.
  • the halogenated hydrocarbon is preferably dichloromethane
  • the aromatic hydrocarbon is preferably toluene
  • the C1-C6 alcohol is preferred.
  • It is ethanol, wherein the volume ratio of dichloromethane to toluene is preferably from 1:3 to 1:1, most preferably 2:3.
  • the temperature condition is 0 to 5 ° C, specifically for example about 5 ° C.
  • the preparation method is carried out by dissolving 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamide free base in In a mixed solvent system of a halogenated hydrocarbon and an aromatic hydrocarbon, hydrochloric acid is added
  • the C1-C6 alcohol solution is stirred at a temperature of -20 ° C to 25 ° C to obtain a solid, which is dried (preferably at room temperature) to obtain a crystalline form H, wherein the halogenated hydrocarbon is preferably dichloromethane, and the aromatic hydrocarbon is preferably toluene.
  • the C1-C6 alcohol is preferably ethanol, wherein the volume ratio of dichloromethane to toluene is preferably from 1:3 to 1:1, and the temperature is preferably from 0 to 5 °C.
  • the stirring time is preferably 12 hours or longer, more preferably 24 hours or longer, further preferably 24 to 60 hours, and most preferably 36 to 48 hours.
  • the 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamide free base is not particularly limited and may be of the formula (I) A solid, semi-solid of the compound, which may also be in the form of a wax or oil of the compound of formula (I).
  • Another object of the present invention is to provide a therapeutically effective amount of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine.
  • a pharmaceutical composition of Form H of the hydrochloride salt and a pharmaceutical excipient typically a therapeutically effective amount of the form H of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine monohydrochloride
  • the pharmaceutical composition or formulation is prepared by mixing or contacting with one or more pharmaceutical excipients, which are prepared in a manner well known in the pharmaceutical art.
  • Form H is suitable for treating human or animal (eg, murine) cancers, including, for example, lung cancer and bronchial cancer; prostate cancer; breast cancer; pancreatic cancer; colon cancer and rectal cancer; thyroid cancer; liver cancer and intrahepatic cholangiocarcinoma Hepatocellular carcinoma; gastric cancer; glioma/glioblastoma; endometrial cancer; melanoma; renal cancer and renal pelvis Bladder cancer; uterine body cancer; cervical cancer; ovarian cancer; multiple myeloma; esophageal cancer; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain cancer; oral cancer and pharyngeal cancer Laryngeal cancer; small bowel cancer
  • the crystalline form H of the present invention and the pharmaceutical composition containing the crystalline form H can be used for the treatment of metastatic breast cancer.
  • the present invention relates to the use of Form H for the preparation of a medicament for the treatment of a condition mediated by PI3K.
  • the condition is a cell proliferative disorder, such as the conditions listed above.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, solubility or dissolution rate The difference can cause the drug to be inefficient and even toxic.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or exhibiting a disease or condition of the disease, disorder or disorder; and (3) Ameliorating the disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a condition or symptom of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual
  • inhibiting the disease for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • PI3K mediated condition refers to a condition that can be beneficially treated by inhibition of PI3K.
  • cell proliferative disorder refers to diseases including, for example, cancer, tumors, hyperplasia, restenosis, cardiac hypertrophy, immune disorders, and inflammation.
  • cancer refers to a cancer disease that can be beneficially treated by inhibiting PI3K, including, for example, lung cancer and bronchial cancer; prostate cancer; breast cancer; pancreatic cancer; colon cancer and rectal cancer; thyroid cancer; liver cancer and intrahepatic cholangiocarcinoma; Cancer; gastric cancer; glioma/glioblastoma; endometrial cancer; melanoma; renal and renal pelvic cancer; bladder cancer; endometrial cancer; cervical cancer; ovarian cancer; multiple myeloma; Carcinoma; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain cancer; oral and pharyngeal cancer; laryngeal cancer; small bowel cancer; non-Hodgkin's lymphoma; melanoma; tumor.
  • pharmaceutically acceptable excipient refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid.
  • materials useful as pharmaceutical excipients are sugars, such as Lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered scutellaria; malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and lauric acid Ethyl ester; agar; buffer, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; is
  • the present invention has the following advantages compared with the prior art:
  • the inventors of the present application have unexpectedly discovered a new crystal form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine hydrochloride. It is stable compared to the prior art crystal form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine hydrochloride. Better sex and low moisture permeability are very important for drug development.
  • Figure 1 is an XRPD pattern of Form H of the present invention
  • Figure 2 is a DSC diagram of Form H of the present invention.
  • Figure 3 is a TGA diagram of Form H of the present invention.
  • Figure 4 is an infrared spectrum of the crystal form H of the present invention.
  • Figure 5 is a DVS diagram of Form H of the present invention.
  • FIG. 6 is a comparison diagram of XRPD of Form H of the present invention before and after DVS test (the upper graph is an XRPD pattern of the crystal form H before the test, and the lower graph is an XRPD pattern of the crystal form H after the test);
  • Figure 7 is a comparison diagram of XRPD of Form H of the present invention before and after being left at 90 °C for 90 days (the upper graph is an XRPD pattern of the crystal form H before leaving, and the lower graph is an XRPD pattern of the crystal form H after standing);
  • Figure 8 is a comparison diagram of XRPD of Form H of the present invention before and after being placed at 25 ° C / 60% relative humidity for 90 days (the upper graph is an XRPD pattern of pre-placement crystal form H, and the lower graph is an XRPD pattern of crystal form H after placement) );
  • Figure 9 is a comparison chart of XRPD of Form H of the present invention before and after being placed at 40 ° C / 75% relative humidity for 90 days (the upper graph is an XRPD pattern of the pre-placement crystal form H, and the lower graph is an XRPD pattern of the crystal form H after standing. ).
  • test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-
  • the starting material of (trifluoromethyl)-2-pyridinamide free base is synthesized by the prior art preparation method and is in solid form.
  • X-ray powder diffraction pattern of the present invention in Panalytical Empyrean X-ray powder diffraction Collected on the instrument.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the X-ray powder diffraction data of the form H obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1. Considering various factors such as d value, low angle, strength, characteristic line and peak shape integrity, The diffraction peaks at 2theta values of 16.63°, 15.78°, and 18.46° are characteristic peaks, and the diffraction peaks at 2theta values of 9.18°, 14.99°, and 7.44° are important peaks, and the 2theta values are 10.46°, 22.66°, and 29.57°. The diffraction peak at the point is the second most important peak.
  • the DSC pattern of Form H is shown in Figure 2. It starts to appear near 81 ° C, 160 ° C, and 263 ° C. The endothermic peak, heating to around 200 ° C began to appear an exothermic peak.
  • the TGA pattern of Form H is shown in Figure 3. When heated to 157 ° C, it has a weight loss gradient of about 7.4%. In summary, Form H is in the form of a hydrate.
  • the infrared spectrum of Form H is shown in Figure 4.
  • the peak of the infrared spectrum (cm -1 , ⁇ 2 cm -1 ) is as follows: 3403.38, 3117.37, 2977.87, 2864.40, 2282.05, 1683.99, 1163.61, 1588.37, 1551.55, 1453.22, 1366.66, 1334.19,1280.40,1246.61,1212.28,1183.02,1150.65,1111.78,1066.82,1041.00,1007.05,974.90,948.74,923.69,861.36,801.86,762.52,704.39,694.03,657.63,622.92,540.66,528.97,474.59.
  • the X-ray powder diffraction data of the form H obtained in this example is shown in Table 3. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 16.68°, 15.81° and 18.49° are characteristic peaks, and the 2theta values are 9.18° and 15.03°. Diffraction at 7.51° The peak is an important peak, and the diffraction peak at 2theta values of 10.52°, 22.62°, and 29.62° is the second most important peak.
  • the crystal form H and the hydrate crystal form Ha disclosed in the patent CN103140479A are each 10.0 mg mixed with 1:1 and added to 0.5 mL of a solvent, and stirred to prepare a suspension, and magnetically stirred at 500 ° C for 24 hours at 5 ° C. Centrifuge and take the solid test XRPD. The results are shown in Table 4.
  • the wettability of the crystalline form H of the present invention was tested by a dynamic moisture adsorption (DVS) instrument.
  • the results showed that the crystalline form H of the present invention was placed under the condition of 80% relative humidity, and the weight gain after the equilibrium was only 1.26%, and the wettability was low.
  • the corresponding DVS diagram is shown in Figure 5.
  • the XRPD test was performed on the crystal form H before and after the DVS test, and the results are shown in Fig. 6. As can be seen from Fig. 6, the crystal forms were identical before and after the test, and no change occurred.
  • the crystal form H of the invention has low wettability, on the one hand, convenient for long-term storage of the medicine; on the other hand, due to low hygroscopicity, no special drying conditions are required in the preparation process, and the preparation of Buparlisib hydrochloride is simplified to some extent. Easy to industrialize with post-treatment process.

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Abstract

涉及一种5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺单盐酸盐的晶型H及其制备方法，晶型H于25℃下的X射线粉末衍射图在2theta值为16.6°±0.2°、15.8°±0.2°、18.5°±0.2°处具有特征峰。该晶型H与现有晶型相比稳定性好、引湿性低，对于该药物开发具有非常重要的意义。

Description

5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型及其制备方法。
背景技术
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型的存在或多晶型形式的数量均不可预见。另外，在什么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式，包括所有的多晶型形式，对于提供具有改善的性能例如储存稳定性和良好溶解度特性等的药物是非常必要的。
5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺(式I化合物)，又名BKM120(Buparlisib)，是由诺华(Novartis)公司研发的乳腺癌新药。目前该药治疗转移性乳腺癌研究正处于III期临床和验证性I/II期临床阶段。BKM120是I类磷酸肌醇-3激酶(PI3K)可逆性抑制剂，研究结果显示其对ER阳性乳腺癌细胞系和种植瘤有抗肿瘤活性，可单独应用或联合内分泌治疗。
Figure PCTCN2016097774-appb-000001
专利CN103140479A公开了式I化合物的结晶形式及其盐的结晶形式。具体的，专利公开了式I化合物半水合物和无水物，式I化合物单盐酸盐的一水合物形式Ha、无水物形式A、形式B及溶剂合物形式Sa、形式Sb、形式Sc、形式Sd及形式Se。从应用角度而言，其中一水合物形式Ha和无水物形式A显然是比溶剂合物更优选的晶型，然而就这二种优选的晶型而言，它们的特性例如稳定性并不能令人满意。
本申请发明人在研究过程中意外发现了以一种新的晶体形式存在的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐，该晶型与已有的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐晶型相比具有更好的稳定性，对于药物开发具有非常重要的意义。
发明内容
本发明的目的之一是提供5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的新晶型，命名为晶型H。
本发明的目的之二是提供所述新晶型H的制备方法和用途。
为实现上述目的，本发明采取如下技术方案：
一种5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺单盐酸盐的晶型H(本发明以下简称晶型H)，其25℃下的X射线粉末衍射图在2theta值为16.6°±0.2°、15.8°±0.2°、18.5°±0.2°处具有特征峰。
进一步的，晶型H的X射线粉末衍射图还在2theta值为9.2°±0.2°、15.0°±0.2°、7.4°±0.2°的一处或多处具有衍射峰，优选地，晶型H的X射线粉末衍射图在2theta值为9.2°±0.2°、15.0°±0.2°、7.4°±0.2°处均具有衍射峰。
进一步的，晶型H的X射线粉末衍射图还在2theta值为10.5°±0.2°、22.7°±0.2°、29.6°±0.2°的一处或多处具有衍射峰，优选地，晶型H的X射线粉 末衍射图在2theta值为10.5°±0.2°、22.7°±0.2°、29.6°±0.2°处均具有衍射峰。
根据本发明的一个具体且优选方面，晶型H在25℃下的X射线粉末衍射图在2theta值为16.6°±0.2°、15.8°±0.2°、18.5°±0.2°、9.2°±0.2°、15.0°±0.2°、7.4°±0.2°、10.5°±0.2°、22.7°±0.2°、29.6°±0.2°处均具有衍射峰。
根据本发明的一个具体且优选方面，晶型H的X射线粉末衍射图基本如图1所示。根据本发明的一个具体方面，晶型H在加热至81℃、160℃、263℃附近开始出现吸热峰，加热至200℃附近开始出现放热峰，其差示扫描量热分析图基本如图2所示。
根据本发明的又一具体方面，晶型H在加热至157℃时，具有约7.4％的重量损失梯度，其热重分析图基本如图3所示。
根据本发明的一个具体方面，本发明的晶型H为水合物。
本发明的目的之二是提供一种晶型H的制备方法，其将5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱与盐酸在溶剂体系中反应，在-20℃-25℃温度下搅拌析晶得到晶型H。
根据本发明的一个优选方面，溶剂体系为卤代烃与芳香烃的混合溶剂体系，其中优选二氯甲烷和甲苯的混合溶剂体系。二氯甲烷和甲苯的体积比优选1∶3至1∶1，最优选2∶3。
根据本发明的又一优选方面，溶剂体系为卤代烃、芳香烃和C1-C6醇三者的混合溶剂体系，其中，卤代烃优选二氯甲烷，芳香烃优选甲苯，C1-C6醇优选为乙醇，其中二氯甲烷和甲苯的体积比优选1∶3至1∶1，最优选2∶3。
优选地，所述温度条件为0～5℃，具体例如约5℃。
优选地，所述制备方法实施如下：将5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱溶解于卤代烃和芳香烃的混合溶剂体系中，加入盐酸 的C1-C6醇溶液，置于温度-20℃-25℃下搅拌，分离获得固体，干燥(优选室温下)，即得晶型H，其中卤代烃优选二氯甲烷，芳香烃优选甲苯，C1-C6醇优选为乙醇，其中二氯甲烷与甲苯的体积比优选为1∶3至1∶1，所述温度优选0～5℃。所述搅拌时间优选为12小时以上，更优选为24小时以上，进一步优选为24～60小时，最优选为36～48小时。
根据本发明，所述5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱没有特别限制，可以是式(I)化合物的固体、半固体，也可以是式(I)化合物的蜡或油形式。
Figure PCTCN2016097774-appb-000002
本发明的另一个目的是提供一种包含有效治疗量的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型H和药用辅料的药用组合物。一般是将治疗有效量的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺单盐酸盐的晶型H与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
更进一步的，本发明晶型H以及含有该晶型H的药物组合物可用于治疗细胞增殖性疾病，诸如PI3K介导的肿瘤及/或癌细胞生长。具体是，晶型H适用于治疗人类或动物(例如鼠类)癌症，包括例如肺癌及支气管癌；前列腺癌；乳癌；胰脏癌；结肠癌及直肠癌；甲状腺癌；肝癌及肝内胆管癌；肝细胞癌；胃癌；神经胶质瘤/神经胶母细胞瘤；子宫内膜癌；黑素瘤；肾癌及肾盂 癌；膀胱癌；子宫体癌；子宫颈癌；卵巢癌；多发性骨髓瘤；食道癌；急性骨髓性白血病；慢性骨髓性白血病；淋巴球性白血病；骨髓白血病；脑癌；口腔癌及咽癌；喉癌；小肠癌；非霍奇金淋巴瘤；黑素瘤；及绒毛结肠腺瘤。
更进一步的，本发明晶型H以及含有该晶型H的药物组合物可用于治疗转移性乳腺癌。
本发明涉及晶型H的用途，其用于制备治疗由PI3K介导的病症的药物。在该用途的一个实施方式中，病症为细胞增殖性疾病，诸如上文所列病症。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度 的不同可以造成药物低效，甚至毒性。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
术语“PI3K介导的病症”指可藉由抑制PI3K有益治疗的病症。
术语“细胞增殖性疾病”指包括例如癌症、肿瘤、增生、再狭窄、心肥大、免疫病症及发炎的疾病。
术语“癌症”指可藉由抑制PI3K有益治疗的癌症疾病，包括例如肺癌及支气管癌；前列腺癌；乳癌；胰脏癌；结肠癌及直肠癌；甲状腺癌；肝癌及肝内胆管癌；肝细胞癌；胃癌；神经胶质瘤/神经胶母细胞瘤；子宫内膜癌；黑素瘤；肾癌及肾盂癌；膀胱癌；子宫体癌；子宫颈癌；卵巢癌；多发性骨髓瘤；食道癌；急性骨髓性白血病；慢性骨髓性白血病；淋巴球性白血病；骨髓白血病；脑癌；口腔癌及咽癌；喉癌；小肠癌；非霍奇金淋巴瘤；黑素瘤；及绒毛结肠腺瘤。
术语“药用辅料”指任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、囊封物质或调配助剂。可用作药用辅料的物质的一些实施例为糖，诸如 乳糖、葡萄糖及蔗糖；淀粉，诸如玉米淀粉及马铃薯淀粉；纤维素及其衍生物，诸如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；粉状黄蓍；麦芽；明胶；滑石；赋形剂，诸如可可脂及栓剂蜡；油，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；二醇，诸如丙二醇；酯，诸如油酸乙酯及月桂酸乙酯；琼脂；缓冲剂，诸如氢氧化镁及氢氧化铝；褐藻酸；无热原质水；等张生理食盐水；林格氏溶液(Ringer′s solution)；乙醇及磷酸盐缓冲溶液，以及其他无毒相同润滑剂，诸如月桂基硫酸钠及硬脂酸镁，以及着色剂、释放剂、涂覆剂、甜味剂、调味剂及芳香剂，防腐剂及抗氧化剂亦可根据配方设计师的判断存在于组合物中。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本申请发明人意外发现了5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的新晶型，其与现有技术的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐晶型相比，稳定性更好，引湿性低，对于药物开发具有非常重要的意义。
附图说明
图1为本发明晶型H的XRPD图；
图2为本发明晶型H的DSC图；
图3为本发明晶型H的TGA图；
图4为本发明晶型H的红外谱图；
图5为本发明晶型H的DVS图；
图6为本发明晶型H在DVS测试前后的XRPD对比图(上图为测试前晶型H的XRPD图，下图为测试后晶型H的XRPD图)；
图7为本发明晶型H在5℃条件下放置90天前后的XRPD对比图(上图为放置前晶型H的XRPD图，下图为放置后晶型H的XRPD图)；
图8为本发明晶型H在25℃/60％相对湿度条件下放置90天前后的XRPD对比图(上图为放置前晶型H的XRPD图，下图为放置后晶型H的XRPD图)；
图9为本发明晶型H在40℃/75％相对湿度条件下放置90天前后的XRPD对比图(上图为放置前晶型H的XRPD图，下图为放置后晶型H的XRPD图)。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱的起始原料通过现有技术制备方法合成得到，为固体形式。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射 仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
Kα1
Figure PCTCN2016097774-appb-000003
1.540598；Kα2
Figure PCTCN2016097774-appb-000004
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气。
实施例1
晶型H的制备方法：
将20.6mg 5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱溶解于0.4mL二氯甲烷和0.6mL甲苯中，加入0.024mL的2mol/L盐酸乙醇溶液，置于5℃搅拌48小时，离心取下层固体，室温下干燥过夜，所得固体为盐酸盐水合物晶型H。
本实施例得到的晶型H的X射线粉末衍射数据如表1所示。其XRPD图如图1。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定， 2theta值为16.63°、15.78°、18.46°处的衍射峰为特征峰，2theta值为9.18°、14.99°、7.44°处的衍射峰为重要的峰，2theta值为10.46°、22.66°、29.57°处的衍射峰为次重要的峰。
表1
2theta d间隔 强度％
7.44 11.89 27.92
9.18 9.64 75.97
10.46 8.46 16.56
14.99 5.91 51.33
15.78 5.62 68.34
16.63 5.33 100.00
18.46 4.81 70.16
19.77 4.49 21.15
20.57 4.32 59.60
22.26 3.99 85.36
22.66 3.92 55.47
23.33 3.81 79.44
23.81 3.74 85.65
23.99 3.71 81.45
24.52 3.63 58.02
25.00 3.56 42.45
26.77 3.33 52.94
27.73 3.22 27.20
28.62 3.12 34.83
29.57 3.02 43.51
30.76 2.91 13.65
31.68 2.82 49.59
32.50 2.75 15.86
34.03 2.63 22.93
36.22 2.48 12.18
37.48 2.40 9.91
38.09 2.36 6.77
晶型H的DSC图如图2所示，在加热81℃、160℃、263℃附近开始出现 吸热峰，加热至200℃附近开始出现放热峰。晶型H的TGA图如图3所示，加热至157℃时，具有约7.4％的重量损失梯度。综合判断，晶型H为水合物形式。
晶型H的红外谱图如图4所示，红外光谱峰值(cm-1，±2cm-1)如下：3403.38，3117.37，2975.87，2860.40，2822.05，1683.99，1631.61，1588.37，1551.55，1453.22，1368.66，1334.19，1280.40，1246.61，1212.28，1183.02，1150.65，1111.78，1066.82，1041.00，1007.05，974.90，948.74，923.69，861.36，801.86，762.52，704.39，694.03，657.63，622.92，540.66，528.97，474.59。
另外，对晶型H中游离碱与盐酸摩尔比进行了实验：取0.993mg晶型H配成乙腈和水(1∶9)混合溶液10mL，通过高效液相色谱测定游离碱的浓度，通过离子色谱测定氯离子的浓度，结果如表2所示。
表2
Figure PCTCN2016097774-appb-000005
结果表明，晶型H中游离碱与盐酸摩尔比为1∶1，确证晶型H为单盐酸盐。
实施例2
晶型H的制备方法：
将100.7mg 5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺游离碱溶解于2.0mL二氯甲烷和3.0mL甲苯中，加入0.12mL的2mol/L盐酸乙醇溶液，置于5℃搅拌48小时，离心取下层固体，室温下干燥过夜，所得固体为晶型H。
本实施例得到的晶型H的X射线粉末衍射数据如表3所示。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为16.68°、15.81°、18.49°处的衍射峰为特征峰，2theta值为9.18°、15.03°、7.51°处的衍射 峰为重要的峰，2theta值为10.52°、22.62°、29.62°处的衍射峰为次重要的峰。
表3
2theta d间隔 强度％
7.51 11.77 40.10
9.18 9.64 100.00
10.52 8.41 16.24
13.11 6.75 2.15
13.38 6.62 1.29
15.03 5.89 30.89
15.81 5.61 45.33
16.68 5.32 58.29
17.68 5.02 3.32
18.04 4.92 3.13
18.49 4.80 39.06
19.33 4.59 5.97
19.92 4.46 2.07
20.64 4.30 4.14
22.07 4.03 9.65
22.62 3.93 18.90
23.39 3.80 8.56
23.86 3.73 10.14
24.63 3.61 7.51
25.10 3.55 5.00
25.91 3.44 7.34
26.86 3.32 6.43
27.22 3.28 5.97
27.81 3.21 3.88
28.61 3.12 11.47
29.62 3.02 14.73
30.48 2.93 5.39
31.75 2.82 12.21
32.63 2.74 3.35
34.09 2.63 4.55
36.26 2.48 4.32
37.51 2.40 2.31
实施例3
晶型H与专利CN103140479A公开的水合物晶型Ha的稳定性对比研究：
取晶型H与专利CN103140479A公开的水合物晶型Ha各10.0mg以1∶1混合加入0.5mL溶剂中搅拌，制成悬浊液，置于5℃以500转每分钟的速率磁力搅拌24小时，离心，取固体测试XRPD。结果如表4。
表4
Figure PCTCN2016097774-appb-000006
结果表明，在试验条件下，专利CN103140479A公开的水合物晶型Ha转为本发明的晶型H，本发明的晶型H比专利CN103140479A公开的水合物晶型Ha更稳定。
实施例4
晶型H与专利CN103140479A公开的无水晶型A的稳定性对比研究：
取10.0mg专利CN103140479A公开的Buparlisib盐酸盐无水晶型A加入0.5ml溶剂中搅拌，制成悬浊液，置于5℃以500转每分钟的速率磁力搅拌，离心，取固体测试XRPD，结果参见表5。
表5晶型H与专利CN103140479A公开的晶型A的转化关系
Figure PCTCN2016097774-appb-000007
结果表明，在试验条件下，CN103140479A公开的无水晶型A转为本发明的晶型H，本发明的晶型H比专利CN103140479A无水晶型A更稳定。
实施例5
采用动态水分吸附(DVS)仪测试本发明晶型H的引湿性，结果表明本发明晶型H在80％相对湿度条件下放置，达到平衡后的增重仅为1.26％，引湿性较低，相应的DVS图如图5所示。另外，对DVS测试前后的晶型H进行XRPD测试，结果见图6，从图6可见，测试前后晶型一致，没有发生改变。
本发明晶型H引湿性较低，一方面，便于药品的长期贮存；另一方面，由于引湿性较低，在制备过程中无需特殊的干燥条件，一定程度上简化了Buparlisib盐酸盐的制备与后处理工艺，易于工业化。
实施例6
对本发明晶型H开展稳定性研究：
分别取三份晶型H样品，分别在5℃条件，25℃/60％相对湿度条件以及40℃/75％相对湿度条件下放置90天，在放置前后分别进行XRPD测试，结果分别参见图7～图9。结果表明，晶型H具有良好的存储稳定性。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (13)

  1. 一种式I化合物的单盐酸盐晶型H，
    Figure PCTCN2016097774-appb-100001
    其特征在于：其25℃下的X射线粉末衍射图在2theta值为16.6°±0.2°、15.8°±0.2°、18.5°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型H，其特征在于：其X射线粉末衍射图还在2theta值为9.2°±0.2°、15.0°±0.2°、7.4°±0.2°的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的晶型H，其特征在于：其X射线粉末衍射图还在2theta值为10.5°±0.2°、22.7°±0.2°、29.6°±0.2°的一处或多处具有衍射峰。
  4. 根据权利要求1所述的晶型H，其特征在于，其X射线粉末衍射图基本上与图1一致。
  5. 根据权利要求1所述的晶型H，其特征在于，所述晶型H为水合物。
  6. 一种如权利要求1～5中任一项权利要求所述的晶型H的制备方法，其特征在于，将式I化合物游离碱与盐酸在溶剂体系中反应，在-20℃-25℃温度条件下搅拌析晶得到所述晶型H。
  7. 根据权利要求6所述的制备方法，其特征在于，所述溶剂体系为卤代烃与芳香烃的混合溶剂体系或卤代烃、芳香烃和C1-C6醇三者的混合溶剂体系。
  8. 根据权利要求7所述的制备方法，其特征在于，所述溶剂体系为二氯甲烷和甲苯的混合溶剂体系或二氯甲烷、甲苯和乙醇的混合溶剂体系。
  9. 根据权利要求8所述的制备方法，其特征在于，所述二氯甲烷和甲苯的体积比介于1∶3至1∶1。
  10. 根据权利要求9所述的制备方法，其特征在于，所述二氯甲烷和甲苯的体积比为2∶3。
  11. 根据权利要求6所述的制备方法，其特征在于，所述温度条件为0～5℃。
  12. 一种药用组合物，其特征在于：包含有效量的权利要求1～5的晶型H及药学上可接受的辅料。
  13. 如权利要求1～5中任一项权利要求所述的式I化合物的单盐酸盐晶型H用于制备治疗转移性乳腺癌药物制剂的用途。
PCT/CN2016/097774 2015-09-21 2016-09-01 5-[2，6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺盐酸盐的晶型及其制备方法 WO2017050111A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012044727A2 (en) * 2010-10-01 2012-04-05 Novartis Ag Manufacturing process for pyrimidine derivatives
WO2014064058A1 (en) * 2012-10-23 2014-05-01 Novartis Ag Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012044727A2 (en) * 2010-10-01 2012-04-05 Novartis Ag Manufacturing process for pyrimidine derivatives
WO2014064058A1 (en) * 2012-10-23 2014-05-01 Novartis Ag Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine

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