WO2016119742A1 - (3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法 - Google Patents

(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法 Download PDF

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WO2016119742A1
WO2016119742A1 PCT/CN2016/072729 CN2016072729W WO2016119742A1 WO 2016119742 A1 WO2016119742 A1 WO 2016119742A1 CN 2016072729 W CN2016072729 W CN 2016072729W WO 2016119742 A1 WO2016119742 A1 WO 2016119742A1
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salt
compound
formula
ray powder
powder diffraction
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French (fr)
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陈敏华
张炎锋
刁小娟
夏楠
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
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • 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 invention relates to the field of chemical medicine, in particular to a salt of (3 ⁇ )-17-(1H-benzimidazol-1-yl)androst-5,16-dien-3-ol and a preparation method thereof.
  • Galeterone chemical name (3 ⁇ )-17-(1H-benzimidazol-1-yl)androst-5,16-dien-3-ol, developed by Tokai Pharmaceutical Co., Ltd. (Tokai), is a A therapeutic drug for a population of castration resistant prostate cancer in prostate cancer.
  • Galeterone works by blocking the antigen receptor signaling pathway in prostate cancer.
  • the antigen receptor signaling pathway promotes prostate cancer growth.
  • this signaling pathway is activated by the binding of male hormones or androgens such as testosterone or the more potent male androgen dihydrotestosterone DHT to the ligand binding domain of the androgen receptor in prostate cancer cells.
  • the drug is currently in clinical phase III and its structure is shown in formula (I):
  • the patent CN103813794A discloses Galeterone amorphous dispersed particles and micronized crystals, and the patent adopts an amorphous dispersion preparation, which improves the solubility in aqueous solution and biological medium compared with the free base crystal form, thereby improving the efficacy of Galeterone.
  • the free amorphous preparation is used to improve the efficacy, the dosage is still very high, and the amorphous has the problem of crystal transformation during storage and transportation, and the preparation of the amorphous dispersion preparation has many disadvantages such as complicated process, time consuming, and the like. So looking for a salt that increases solubility and lowers the dose is significant.
  • the system has been systematically screened and found that several salts have an unintended effect, and the dosage can be lowered in the future while satisfying the requirements of the drug effect, the preparation process is more convenient, the patient compliance is stronger, and the potential high dose is lowered.
  • the side effects caused have important drug development value.
  • the crystalline form of the named phosphate is the phosphate crystal form A
  • the crystalline form of the tartrate is the tartrate form A
  • the crystalline form of the citrate is the citrate form A.
  • the present invention adopts the following technical solutions:
  • the salt is a phosphate in crystalline form, a tartrate salt in crystalline form or a citrate salt in crystalline form.
  • the molar ratio of the compound of the formula (I) to the acid is 1:1.
  • the salt is a phosphate and is crystalline form A, and its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.0 ° ⁇ 0.2 °, 20.3 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.8 ° ⁇ 0.2 °, 5.2 ° ⁇ 0.2 °, and 14.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 16.1 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, and 24.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • the phosphate crystal form A provided by the present invention starts to have an endothermic peak near heating to 200 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 2 .
  • the phosphate crystal form A provided by the present invention has a weight loss gradient of about 1.9% when heated to 175 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 3 .
  • the salt is a tartrate salt and is crystalline form A, and its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 18.1 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, and 15.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.5 ° ⁇ 0.2 °, 6.2 ° ⁇ 0.2 °, and 21.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 14.3 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 °, and 10.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 7.
  • the tartrate salt form A provided by the present invention starts to have an endothermic peak near heating to 188 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 8 .
  • the tartrate salt form A provided by the present invention has a weight loss gradient of about 1.2% when heated to 175 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • the salt is a citrate salt and is crystalline form A, and its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 18.0° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 16.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.5 ° ⁇ 0.2 °, 18.9 ° ⁇ 0.2 °, and 27.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 15.9 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, and 19.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of FIG.
  • the citrate crystal form A provided by the present invention starts to have an endothermic peak near heating to 190 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 14 .
  • the citrate form A provided by the present invention has a weight loss gradient of about 1.7% when heated to 174 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • the molar ratio of the compound of the formula (I) to the acid is from 1:1 to 2.
  • the solvent includes, but is not limited to, a combination of one or more of an alcohol, a ketone, an ester, an aromatic hydrocarbon, a halogenated hydrocarbon, a nitrile, a nitroalkane, a cyclic ether, and an aliphatic hydrocarbon solvent.
  • the solvent is a combination of one or more selected from the group consisting of acetonitrile, ethyl acetate, acetone, and tetrahydrofuran.
  • reaction temperature is 0 to 40 °C.
  • a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, said active ingredient being a salt of said compound of formula (I).
  • the invention further relates to the use of a salt of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the present invention has the following advantages compared with the prior art:
  • the inventors of the present invention screened and studied the salt formation of the compound of the formula (I), found a new salt type suitable for drug development, improved the solubility of the drug, and avoided the complicated and time-consuming preparation of the amorphous dispersion preparation. Process and the risk of amorphous crystals.
  • the phosphate, tartrate and citrate salts of the compound of the formula (I) provided by the invention have high crystal form solubility, low wettability, good stability, simple preparation process, easy operation, and are suitable for long-term storage and industrialization. Production provides a better choice for the subsequent development of the drug.
  • the crystal form of the three salts prepared by the present invention has higher solubility than the micronized crystal in the patent CN103813794A (named as free base crystal form A in the present invention), has important significance for improving bioavailability, and avoids complicated and time consuming.
  • the expensive micronization technology has strong economic value for drug development and industrial production.
  • the crystalline form of the phosphate, tartrate, citrate salt of the compound of formula (I) provided by the present invention can be used for the preparation of a medicament for treating cancer, in particular for the preparation of a medicament for treating prostate cancer.
  • the pharmaceutical composition is prepared by using the crystalline form of the phosphate, tartrate and citrate of the compound of the formula (I) as an active ingredient, and adding a common auxiliary material for the medicine.
  • Figure 1 is an XRPD pattern of phosphate crystal form A
  • Figure 2 is a DSC chart of the phosphate crystal form A
  • Figure 3 is a TGA diagram of the phosphate crystal form A
  • Figure 4 is an XRPD pattern of phosphate crystal form A before and after being placed at 5 ° C for 90 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after 90 days);
  • Figure 5 is an XRPD pattern of phosphate crystal form A before and after being placed at 25 ° C and 60% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after 90 days);
  • Figure 6 is an XRPD pattern of the phosphate crystal form A before and after being placed at 40 ° C, 75% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after 90 days);
  • Figure 7 is an XRPD pattern of the tartrate salt form A
  • Figure 8 is a DSC chart of the tartrate salt form A
  • Figure 9 is a TGA diagram of the tartrate salt form A
  • Figure 10 is a H 1 -NMR chart of the tartrate salt form A
  • Figure 11 is an XRPD pattern of the tartrate salt form A before and after being placed at 5 ° C for 90 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after 90 days);
  • Figure 12 is an XRPD pattern of the tartrate salt form A before and after being placed at 25 ° C and 60% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after 90 days);
  • Figure 13 is an XRPD pattern of the tartrate salt form A before and after being placed at 40 ° C, 75% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after 90 days of placement);
  • Figure 14 is an XRPD pattern of citrate crystal form A
  • Figure 15 is a DSC chart of citrate crystal form A
  • Figure 16 is a TGA diagram of citrate crystal form A
  • Figure 17 is a H 1 -NMR chart of citrate form A
  • Figure 18 is an XRPD pattern of citrate form A before and after being placed at 5 ° C for 90 days (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after 90 days);
  • Figure 19 is an XRPD pattern of citrate form A before and after being placed at 25 ° C, 60% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after 90 days);
  • Figure 20 is an XRPD pattern of citrate form A before and after being placed at 40 ° C, 75% relative humidity for 90 days (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after 90 days);
  • Figure 21 is a DVS diagram of the phosphate crystal form A
  • Figure 22 is a DVS diagram of the tartrate salt form A
  • Figure 23 is a DVS diagram of citrate crystal form A
  • Figure 24 is an XRPD diagram before and after the wettability test of the phosphate crystal form A (the upper graph shows the XRPD pattern before the wettability test, and the lower graph shows the XRPD pattern after the wettability test);
  • Figure 25 is an XRPD diagram before and after the wettability test of the tartrate salt form A (the figure above shows the XRPD pattern before the wettability test, and the figure below shows the XRPD pattern after the wettability test);
  • Figure 26 is an XRPD diagram before and after the wettability test of the citrate crystal form A (the upper graph is an XRPD pattern before the wettability test, and the lower graph is an XRPD pattern after the wettability test);
  • Figure 27 is an XRPD pattern of amorphous L-ascorbate.
  • the phosphoric acid to which the present invention relates is an analytically pure grade aqueous phosphoric acid solution obtained by a commercially available method having a mass fraction of 35%.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TAQ2000.
  • 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 collected on a TAQ5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorption instrument are as follows: temperature: 25 ° C
  • Relative humidity range 0%RH-95%RH
  • the crystal form A of the phosphate was allowed to stand at 5 ° C for 90 days, and then subjected to X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG. 4 .
  • the crystal form A of the phosphate was allowed to stand under conditions of 25 ° C and 60% relative humidity for 90 days, and subjected to an X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG.
  • the crystal form A of the phosphate was allowed to stand under the conditions of 40 ° C and 75% relative humidity for 90 days, and subjected to an X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG. 6 .
  • the resulting solid is crystalline Form A of phosphate, and its X-ray powder diffraction data includes, but is not limited to, Table 2 data.
  • the resulting solid was crystalline form A of the tartrate salt, and its X-ray powder diffraction data includes, but is not limited to, Table 3 data. Its XRPD diagram is shown in Fig. 7, its DSC diagram is shown in Fig. 8, and its TGA diagram is shown in Fig. 9.
  • the H 1 -NMR chart of the tartrate salt form A is shown in Figure 10, and the nuclear magnetic data indicates that the salt has a molar ratio of the compound of the formula (I) to tartaric acid of 1:1.
  • the crystal form A of the tartrate salt was subjected to an X-ray powder diffraction test after leaving it at 5 ° C for 90 days, and the obtained XRPD pattern is shown in FIG.
  • the crystal form A of the tartrate salt was subjected to an X-ray powder diffraction test after leaving it at 25 ° C and 60% relative humidity for 90 days, and the obtained XRPD pattern is shown in FIG.
  • the crystal form A of the tartrate salt was subjected to an X-ray powder diffraction test after leaving it at 40 ° C and 75% relative humidity for 90 days, and the obtained XRPD pattern is shown in FIG.
  • the resulting solid was crystalline form A of the tartrate salt, and its X-ray powder diffraction data included, but is not limited to, Table 4 data.
  • the H 1 -NMR chart of the citrate form A is shown in Figure 17, and the nuclear magnetic data indicates that the salt has a molar ratio of the compound of the formula (I) to citric acid of 1:1.
  • the crystal form A of citrate was allowed to stand at 5 ° C for 90 days, and subjected to X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG.
  • the crystal form A of citrate was allowed to stand under conditions of 25 ° C and 60% relative humidity for 90 days, and subjected to X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG.
  • the crystal form A of citrate was allowed to stand under conditions of 40 ° C and 75% relative humidity for 90 days, and subjected to X-ray powder diffraction test, and the obtained XRPD pattern is shown in FIG.
  • the resulting solid was crystalline form A of citrate, and its X-ray powder diffraction data included, but is not limited to, Table 6 data.
  • the resulting solid is crystalline form A of citrate, and its X-ray powder diffraction data includes, but is not limited to, Table 7 data.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the phosphate crystal form A prepared in Example 1, the tartrate salt form A prepared in Example 3, the citrate salt form A prepared in Example 5, and the patent CN103813794A free base form A sample were respectively used in high purity water. Prepared as a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 24 hours. The experimental results are shown in Table 9.

Abstract

本发明涉及(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的磷酸盐、酒石酸盐、柠檬酸盐的结晶形式及其制备方法。本发明的式(I)化合物的磷酸盐、酒石酸盐、柠檬酸盐的结晶形式，具有溶解度高、引湿性低、稳定性好、工艺简单易于操作等有利性能，适合储存和工业化生产，对未来该药物的优化和开发具有重要价值。

Description

(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法。
背景技术
Galeterone，化学名称为(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇，由日本东海制药公司(Tokai)研发，是一种针对***癌中的去势抗性(castration resistant prostate cancer)群体的治疗药物。Galeterone通过截断***癌的抗原受体信号通路发挥作用。抗原受体信号通路促进了***癌生长。一般而言，这种信号通路通过男性荷尔蒙或者雄激素(比如睾酮或者更强效的男性雄激素双氢睾酮DHT)与***癌细胞中的雄激素受体的配体结合域相结合来激活。该药物目前处在临床III期阶段，其结构如式(I)所示：
Figure PCTCN2016072729-appb-000001
目前，专利CN103813794A公开了Galeterone的无定形分散颗粒及微粉化晶体，专利采用无定形分散制剂，相比其游离碱晶型提高了在水溶液及生物介质中的溶解度，从而提高了Galeterone的药效。然而即使使用游离态无定形的制剂来提高药效，其剂量仍然十分之高，而无定形存在储存运输过程中的转晶问题，且无定形分散制剂的制备存在工艺复杂，耗时等许多缺点，所以寻找一个能够提高溶解度且降低剂量的盐意义重大。
发明内容
本发明经过***的筛选，发现几种盐具有意向不到的效果，在满足药效要求的同时可以使得未来剂量降低，制剂工艺更加方便，病人顺应性也会更强，并降低潜在的高剂量引起的副作用，具有重要的药物开发价值。
本发明的目的是提供一种适于药物研究和工业化生产的式(I)化合物的盐，包括磷酸盐、酒石酸盐或柠檬酸盐，所提供的磷酸盐、酒石酸盐或柠檬酸盐为结晶形式，本发明中命名磷酸盐的结晶形式为磷酸盐晶型A，酒石酸盐的结晶形式为酒石酸盐晶型A，柠檬酸盐的结晶形式为柠檬酸盐晶型A。
为实现上述目的，本发明采取如下技术方案：
式(I)化合物(3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇与多种酸形成的盐，
Figure PCTCN2016072729-appb-000002
所述的盐为结晶形式的磷酸盐、结晶形式的酒石酸盐或结晶形式的柠檬酸盐。
进一步地，所述式(I)化合物与酸的摩尔比为1∶1。
进一步地，所述的盐为磷酸盐且为晶型A，其X射线粉末衍射图在2theta值为17.0°±0.2°、20.3°±0.2°、21.4°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为17.8°±0.2°、5.2°±0.2°、14.3°±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为16.1°±0.2°、25.5°±0.2°、24.9°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图1一致。
本发明提供的磷酸盐晶型A，在加热至200℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
本发明提供的磷酸盐晶型A，在加热至175℃时，具有约1.9％的重量损失梯度，其热重分析图基本如图3所示。
进一步地，所述的盐为酒石酸盐且为晶型A，其X射线粉末衍射图在2theta值为18.1°±0.2°、16.0°±0.2°、15.7°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为20.5°±0.2°、6.2°±0.2°、21.1°±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为14.3°±0.2°、22.9°±0.2°、10.6°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图7一致。
本发明提供的酒石酸盐晶型A，在加热至188℃附近开始出现吸热峰，其差示扫描量热分析图基本如图8所示。
本发明提供的酒石酸盐晶型A，在加热至175℃时，具有约1.2％的重量损失梯度，其热重分析图基本如图9所示。
进一步地，所述的盐为柠檬酸盐且为晶型A，其X射线粉末衍射图在2theta值为18.0°±0.2°、20.3°±0.2°、16.8°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为17.5°±0.2°、18.9°±0.2°、27.0°±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为15.9°±0.2°、18.3°±0.2°、19.6°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图13一致。
本发明提供的柠檬酸盐晶型A，在加热至190℃附近开始出现吸热峰，其差示扫描量热分析图基本如图14所示。
本发明提供的柠檬酸盐晶型A，在加热至174℃时，具有约1.7％的重量损失梯度，其热重分析图基本如图15所示。
一种制备所述的式(I)化合物的盐的方法，包括使式(I)化合物与酸在一种溶剂或多种溶剂的混合体系内反应，搅拌析晶得到；所述的酸是磷酸、酒石酸或柠檬酸。
进一步地，所述式(I)化合物与所述酸的投料摩尔比为1∶1～2。
进一步地，所述的溶剂包括但不限于醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚，脂肪烃类溶剂中的一种或多种的组合。
更进一步地，所述的溶剂为选自乙腈、乙酸乙酯、丙酮、四氢呋喃中的一种或多种的组合。
进一步地，所述的反应温度为0～40℃。
一种药物组合物，包括活性成分和药学上可接受的载体，所述的活性成分为所述的式(I)化合物的盐。
本发明还涉及所述的式(I)化合物的盐在制备治疗癌症药物中的用途。
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：
本发明的发明人对式(I)化合物进行了成盐筛选和研究，找到了适于药物开发的新的盐型，提高了药物的溶解度，且避免了制备无定形分散制剂复杂、耗时的工艺以及无定形容易转晶的风险。
本发明提供的式(I)化合物的磷酸盐、酒石酸盐、柠檬酸盐这三种盐的新晶型溶解度高、引湿性低、稳定性好、制备工艺简单、易于操作、适合长期储存和工业化生产，为药物的后续开发提供了更好的选择。本发明制备的三种盐的结晶形式比专利CN103813794A中的微粉化晶体(本发明中命名为游离碱晶型A)溶解度高，对提高生物利用度具有重要的意义，并且避免了复杂、耗时、昂贵的微粉化技术，对药物开发和工业化生产具有很强的经济价值。
本发明提供的式(I)化合物的磷酸盐、酒石酸盐、柠檬酸盐的结晶形式可用于治疗癌症药物的制备，特别是用于治***癌药物的制备。
药用组合物，是以式(I)化合物的磷酸盐、酒石酸盐、柠檬酸盐的结晶形式为活性成分，添加药物常用辅料制备而成。
附图说明
图1为磷酸盐晶型A的XRPD图；
图2为磷酸盐晶型A的DSC图；
图3为磷酸盐晶型A的TGA图；
图4为磷酸盐晶型A在5℃条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图5为磷酸盐晶型A在25℃、60％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图6为磷酸盐晶型A在40℃、75％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图7为酒石酸盐晶型A的XRPD图；
图8为酒石酸盐晶型A的DSC图；
图9为酒石酸盐晶型A的TGA图；
图10为酒石酸盐晶型A的H1-NMR图；
图11为酒石酸盐晶型A在5℃条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图12为酒石酸盐晶型A在25℃、60％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图13为酒石酸盐晶型A在40℃、75％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图14为柠檬酸盐晶型A的XRPD图；
图15为柠檬酸盐晶型A的DSC图；
图16为柠檬酸盐晶型A的TGA图；
图17为柠檬酸盐晶型A的H1-NMR图；
图18为柠檬酸盐晶型A在5℃条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图19为柠檬酸盐晶型A在25℃、60％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图20为柠檬酸盐晶型A在40℃、75％相对湿度条件下放置90天前后的XRPD图(上图为放置前的XRPD图，下图为放置90天后的XRPD图)；
图21为磷酸盐晶型A的DVS图；
图22为酒石酸盐晶型A的DVS图；
图23为柠檬酸盐晶型A的DVS图；
图24为磷酸盐晶型A的引湿性试验前后XRPD图(上图为引湿性试验前的XRPD图，下图为引湿性试验后的XRPD图)；
图25为酒石酸盐晶型A的引湿性试验前后XRPD图(上图为引湿性试验前的XRPD图，下图为引湿性试验后的XRPD图)；
图26为柠檬酸盐晶型A的引湿性试验前后XRPD图(上图为引湿性试验前的XRPD图，下图为引湿性试验后的XRPD图)；
图27为L-抗坏血酸盐无定形的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。
本发明涉及的磷酸是指通过市售方式获得的，质量分数为35％的分析纯级别的磷酸水溶液。
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
H1-NMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical EmpyreanX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
Figure PCTCN2016072729-appb-000003
1.540598；
Figure PCTCN2016072729-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TAQ2000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TAQ5000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
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：温度：25℃
载气，流速：N2，200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
实施例1
式(I)化合物的磷酸盐晶型A的制备方法：
将206.1mg式(I)化合物悬浮于10mL乙腈中，加入0.044mL的质量分数为35％的磷酸水溶液，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为磷酸盐的晶型A，其X射线粉末衍射数据包括但不限于表1的数据。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
将磷酸盐的晶型A在5℃条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图4所示。
将磷酸盐的晶型A在25℃、60％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图5所示。
将磷酸盐的晶型A在40℃、75％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图6所示。
表1
2theta d间隔 强度％
5.19 17.04 36.23
7.10 12.46 11.56
10.24 8.64 2.59
13.24 6.69 7.15
14.33 6.18 30.31
15.66 5.66 9.17
16.11 5.50 28.32
17.04 5.20 100.00
17.83 4.98 37.38
19.64 4.52 5.51
20.28 4.38 44.64
20.72 4.29 16.60
21.38 4.16 38.11
22.43 3.96 8.81
23.68 3.76 3.62
24.24 3.67 12.42
24.86 3.58 16.61
25.06 3.55 15.51
25.55 3.49 21.89
26.09 3.42 7.51
27.45 3.25 4.13
27.85 3.20 3.30
28.61 3.12 3.89
30.07 2.97 3.57
31.07 2.88 5.25
34.87 2.57 1.37
38.53 2.34 2.08
实施例2
式(I)化合物磷酸盐晶型A的制备方法：
将10.1mg式(I)化合物悬浮于0.5mL乙酸乙酯中，加入0.002mL的质量分数为35％的磷酸溶液，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为磷酸盐的晶型A，其X射线粉末衍射数据包括但不限于表2数据。
表2
2theta d间隔 强度％
3.03 29.12 11.82
5.07 17.44 60.71
6.96 12.71 17.77
7.05 12.54 14.98
10.25 8.63 3.70
13.20 6.71 7.16
14.30 6.19 30.42
14.69 6.03 4.51
15.35 5.77 6.22
15.63 5.67 7.44
16.10 5.51 42.23
17.04 5.20 100.00
17.83 4.97 46.66
18.97 4.68 0.87
19.36 4.59 2.36
19.67 4.51 7.51
20.31 4.37 47.08
20.55 4.32 17.38
20.75 4.28 17.83
21.42 4.15 36.70
22.47 3.96 11.65
23.09 3.85 1.31
23.73 3.75 1.47
24.31 3.66 10.64
24.92 3.57 17.23
25.10 3.55 13.52
25.60 3.48 19.55
26.15 3.41 7.99
27.03 3.30 0.78
27.55 3.24 3.99
27.94 3.19 2.55
28.30 3.15 2.29
28.80 3.10 4.84
29.44 3.03 10.21
30.20 2.96 3.59
31.17 2.87 7.75
32.27 2.77 1.68
32.96 2.72 1.95
33.39 2.68 0.53
34.29 2.62 0.72
35.04 2.56 0.98
36.06 2.49 1.52
36.35 2.47 1.88
36.98 2.43 1.05
37.80 2.38 1.78
38.73 2.33 2.58
39.55 2.28 1.64
实施例3
式(I)化合物酒石酸盐晶型A的制备方法：
将10.5mg式(I)化合物悬浮于0.5mL丙酮中，加入5.8mg的酒石酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为酒石酸盐的晶型A，其X射线粉末衍射数据包括但不限于表3数据。其XRPD图如图7，其DSC图如图8，其TGA图如图9。
酒石酸盐晶型A的H1-NMR图如图10所示，核磁数据表明该盐为式(I)化合物与酒石酸的摩尔比为1∶1。
将酒石酸盐的晶型A在5℃条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图11所示。
将酒石酸盐的晶型A在25℃、60％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图12所示。
将酒石酸盐的晶型A在40℃、75％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图13所示。
表3
2theta d间隔 强度％
6.22 14.22 22.23
8.35 10.59 1.11
10.60 8.34 11.59
11.94 7.41 11.41
12.26 7.22 5.86
12.62 7.02 1.77
12.82 6.91 3.49
13.20 6.71 5.28
13.90 6.37 4.78
14.31 6.19 13.86
14.87 5.96 10.63
15.67 5.66 30.72
15.98 5.54 76.64
16.26 5.45 8.66
17.69 5.01 11.17
18.08 4.91 100.00
18.36 4.83 6.82
18.88 4.70 6.76
19.03 4.66 3.31
19.80 4.48 3.38
20.23 4.39 1.74
20.47 4.34 22.38
20.72 4.29 5.28
21.06 4.22 14.73
21.96 4.05 4.64
22.19 4.01 2.53
22.71 3.92 12.07
22.88 3.89 12.38
23.67 3.76 2.91
23.98 3.71 3.74
24.16 3.68 2.22
24.57 3.62 3.70
25.54 3.49 7.93
25.84 3.45 9.60
26.05 3.42 4.80
26.11 3.41 4.32
26.62 3.35 2.97
26.90 3.31 1.70
27.23 3.27 1.61
27.68 3.22 4.66
28.17 3.17 1.49
28.72 3.11 8.83
29.29 3.05 8.27
29.44 3.03 6.96
29.91 2.99 0.87
30.17 2.96 0.98
30.51 2.93 2.40
31.55 2.83 5.86
31.70 2.82 8.38
32.22 2.78 2.16
32.45 2.76 4.07
33.03 2.71 1.46
33.63 2.67 2.16
34.13 2.63 0.76
34.75 2.58 5.27
35.58 2.52 1.20
35.95 2.50 2.96
36.72 2.45 0.43
37.29 2.41 1.49
37.69 2.39 1.16
38.85 2.32 1.66
39.47 2.28 1.59
实施例4
式(I)化合物酒石酸盐晶型A的制备方法：
将202.7mg式(I)化合物悬浮于10mL乙腈中，加入119.0mg的酒石酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为酒石酸盐的晶型A，其X射线粉末衍射数据包括但不限于表4数据。
表4
2theta d间隔 强度％
3.12 28.35 2.90
6.31 14.01 54.89
8.43 10.49 2.23
10.65 8.30 7.16
12.00 7.38 9.76
12.30 7.19 11.08
12.65 7.00 4.97
12.85 6.89 2.47
13.23 6.69 5.56
13.93 6.36 3.69
14.33 6.18 11.20
14.90 5.95 19.07
15.69 5.65 34.45
16.00 5.54 82.11
16.28 5.44 9.36
17.70 5.01 18.96
18.08 4.91 100.00
18.37 4.83 8.45
18.87 4.70 8.47
19.04 4.66 6.71
19.80 4.48 2.43
20.46 4.34 22.32
21.05 4.22 12.28
21.93 4.05 2.05
22.17 4.01 1.67
22.69 3.92 11.16
22.84 3.89 7.29
23.63 3.76 4.23
23.95 3.72 1.80
24.54 3.63 3.68
25.49 3.49 12.93
25.79 3.45 10.18
26.63 3.35 1.93
27.61 3.23 1.82
28.65 3.12 9.38
29.22 3.05 4.83
29.32 3.05 4.59
30.49 2.93 1.82
31.62 2.83 5.62
32.32 2.77 1.94
34.64 2.59 5.32
35.85 2.51 2.02
37.45 2.40 0.45
实施例5
式(I)化合物柠檬酸盐晶型A的制备方法：
将10.5mg式(I)化合物悬浮于0.5mL丙酮中，加入5.8mg的柠檬酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为柠檬酸盐的晶型A，其X射线粉末衍射数据包括但不限于表5数据。其XRPD图如图14，其DSC图如图15，其TGA图如图16。
柠檬酸盐晶型A的H1-NMR图如图17所示，核磁数据表明该盐为式(I)化合物与柠檬酸的摩尔比为1∶1。
将柠檬酸盐的晶型A在5℃条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图18所示。
将柠檬酸盐的晶型A在25℃、60％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图19所示。
将柠檬酸盐的晶型A在40℃、75％相对湿度条件下放置90天后进行X射线粉末衍射测试，所得XRPD图如图20所示。
表5
2theta d间隔 强度％
5.97 14.80 9.31
10.09 8.77 2.53
10.62 8.33 22.13
12.10 7.32 9.29
13.31 6.65 3.68
14.24 6.22 31.42
14.74 6.01 21.14
15.24 5.81 17.77
15.62 5.67 5.49
15.85 5.59 42.62
16.78 5.28 80.58
17.54 5.06 52.05
17.95 4.94 100.00
18.28 4.85 36.97
18.88 4.70 51.61
19.61 4.53 32.50
20.34 4.37 80.79
20.73 4.28 10.93
21.04 4.22 15.95
21.32 4.17 3.93
22.13 4.01 30.22
22.22 4.01 21.31
22.75 3.91 7.25
23.37 3.80 17.37
24.45 3.64 3.34
25.05 3.55 1.41
25.34 3.51 2.48
25.69 3.47 4.76
26.54 3.36 2.02
27.03 3.30 49.89
27.44 3.25 0.96
28.18 3.16 3.34
28.55 3.12 2.12
29.08 3.07 3.48
29.51 3.02 19.11
30.32 2.95 9.20
31.08 2.87 15.23
31.80 2.81 4.34
32.36 2.76 7.48
32.57 2.75 8.86
33.74 2.65 9.86
34.21 2.62 4.61
34.41 2.60 4.99
35.35 2.54 0.70
35.73 2.51 1.84
35.98 2.49 6.68
36.05 2.49 7.21
36.49 2.46 4.05
36.95 2.43 1.09
37.31 2.41 7.90
38.15 2.36 6.88
38.46 2.34 3.60
39.26 2.29 5.70
实施例6
式(I)化合物柠檬酸盐晶型A的制备方法：
将202.7mg式(I)化合物悬浮于10mL乙腈中，加入119.0mg的柠檬酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为柠檬酸盐的晶型A，其X射线粉末衍射数据包括但不限于表6数据。
表6
2theta d间隔 强度％
6.06 14.59 8.26
10.09 8.76 1.54
10.67 8.29 18.76
12.13 7.30 9.89
13.34 6.64 7.45
14.26 6.21 41.46
15.24 5.82 1.50
15.87 5.58 3.89
16.78 5.28 100.00
17.46 5.08 14.18
17.94 4.94 12.29
18.27 4.86 7.55
18.87 4.70 8.68
19.57 4.54 36.17
20.32 4.37 18.38
20.71 4.29 14.36
21.01 4.23 2.90
22.10 4.02 5.77
22.70 3.92 4.01
23.33 3.81 2.94
24.41 3.65 1.76
25.63 3.48 5.42
26.44 3.37 1.42
26.96 3.31 14.92
28.10 3.18 2.44
29.39 3.04 5.54
31.07 2.88 1.46
31.70 2.82 1.87
32.34 2.77 2.75
34.15 2.63 1.46
37.21 2.42 1.21
38.18 2.36 0.34
实施例7
式(I)化合物柠檬酸盐晶型A的制备方法：
将202.1mg式(I)化合物悬浮于10mL四氢呋喃中，加入119.2mg的柠檬酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为柠檬酸盐的晶型A，其X射线粉末衍射数据包括但不限于表7数据。
表7
2theta d间隔 强度％
6.03 14.65 14.34
10.10 8.75 2.68
10.65 8.31 26.77
12.12 7.30 11.05
13.34 6.64 6.69
14.25 6.21 38.66
15.19 5.83 1.30
15.83 5.60 3.53
16.78 5.28 100.00
17.48 5.07 16.27
17.90 4.95 14.27
18.24 4.86 8.41
18.82 4.71 8.95
19.58 4.53 36.06
20.30 4.37 20.15
20.73 4.28 14.3
20.98 4.24 3.07
22.09 4.02 6.21
22.72 3.91 4.84
23.30 3.82 4.68
24.42 3.65 2.32
25.64 3.47 6.78
26.47 3.37 1.81
26.95 3.31 18.36
28.12 3.17 2.82
29.37 3.04 3.95
30.21 2.96 0.97
31.11 2.87 1.79
31.70 2.82 1.85
32.36 2.77 3.84
34.18 2.62 1.90
37.26 2.41 0.90
38.21 2.36 0.81
39.07 2.31 0.61
实施例8
磷酸盐晶型A、酒石酸盐晶型A、柠檬酸盐晶型A的引湿性研究：
分别取10mg本发明的实施例1制得的磷酸盐晶型A、实施例3制得的酒石酸盐晶型A、实施例5制得的柠檬酸盐晶型A进行动态水分吸附(DVS)测试。结果如表8所示，磷酸盐晶型A的DVS如图21所示，酒石酸盐晶型A的DVS如图22所示，柠檬酸盐晶型A的DVS如图23所示。磷酸盐晶型A在80％相对湿度条件下进行引湿性试验前后的XRPD图如图24所示，酒石酸盐晶型A在80％相对湿度条件下进行引湿性试验前后的XRPD图如图25所示，柠檬酸盐晶型A在80％相对湿度条件下进行引湿性试验前后的XRPD图如图26所示。
表8
盐的类型 80％相对湿度的增重 DVS前后晶型变化
磷酸盐晶型A 1.47％ 不变(图24)
酒石酸盐晶型A 0.39％ 不变(图25)
柠檬酸盐晶型A 0.79％ 不变(图26)
结果表明，磷酸盐晶型A、酒石酸盐晶型A、柠檬酸盐晶型A在80％相对湿度下引湿性低，且晶型在高湿度下不易转变，便于药品的长期储存。
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例9
本发明中的磷酸盐、酒石酸盐、柠檬酸盐的结晶形式与专利CN103813794A晶型A溶解度对比研究：
将实施例1中制备得到的磷酸盐晶型A、实施例3制备得到的酒石酸盐晶型A、实施例5制备得到的柠檬酸盐晶型A与专利CN103813794A游离碱晶型A样品分别用高纯水配制成饱和溶液，在24个小时后采用高效液相色谱测定饱和溶液中样品的含量。实验结果如表9所示。
表9
Figure PCTCN2016072729-appb-000005
通过上述对比结果可以看出，在高纯水中放置24个小时后本发明的磷酸盐晶型A、酒石酸盐晶型A、柠檬酸盐晶型A与专利CN103813794A游离碱晶型A相比，溶解度均得到提高。
对比例1
L-抗坏血酸盐无定形的制备方法：
将10.0mg式(I)化合物悬浮于0.5mL四氢呋喃中，加入4.7mg的L-抗坏血酸，室温下搅拌反应12小时，得到的盐为无定形。本实施例得到的晶型XRPD图如图27。
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 (20)

  1. 式(I)化合物(3)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇与多种酸形成的盐，
    Figure PCTCN2016072729-appb-100001
    其特征在于，所述的盐为结晶形式的磷酸盐、结晶形式的酒石酸盐或结晶形式的柠檬酸盐。
  2. 根据权利要求1所述的式(I)化合物的盐，其特征在于：所述的盐为磷酸盐且为晶型A，其X射线粉末衍射图在2theta值为17.0°±0.2°、20.3°±0.2°、21.4°±0.2°处具有特征峰。
  3. 根据权利要求2所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为17.8°±0.2°、5.2°±0.2°、14.3°±0.2°处具有特征峰。
  4. 根据权利要求3所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为16.1°±0.2°、25.5°±0.2°、24.9°±0.2°处具有特征峰。
  5. 根据权利要求2所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图基本上与图1一致。
  6. 根据权利要求1所述的式(I)化合物的盐，其特征在于，所述的盐为酒石酸盐且为晶型A，其X射线粉末衍射图在2theta值为18.1°±0.2°、16.0°±0.2°、15.7°±0.2°处具有特征峰。
  7. 根据权利要求6所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为20.5°±0.2°、6.2°±0.2°、21.1°±0.2°处具有特征峰。
  8. 根据权利要求7所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为14.3°±0.2°、22.9°±0.2°、10.6°±0.2°处具有特征峰。
  9. 根据权利要求6所述的式(I)化合物的盐，其特征在于，其X射线粉末 衍射图基本上与图7一致。
  10. 根据权利要求1所述的式(I)化合物的盐，其特征在于，所述的盐为柠檬酸盐且为晶型A，其X射线粉末衍射图在2theta值为18.0°±0.2°、20.3°±0.2°、16.8°±0.2°处具有特征峰。
  11. 根据权利要求10所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为17.5°±0.2°、18.9°±0.2°、27.0°±0.2°处具有特征峰。
  12. 根据权利要求11所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图在2theta值为15.9°±0.2°、18.3°±0.2°、19.6°±0.2°处具有特征峰。
  13. 根据权利要求10所述的式(I)化合物的盐，其特征在于，其X射线粉末衍射图基本上与图14一致。
  14. 一种制备权利要求1至13中任一项所述的式(I)化合物的盐的方法，其特征在于，包括使式(I)化合物与酸在一种溶剂或多种溶剂的混合体系内反应，搅拌析晶得到；所述的酸是磷酸、酒石酸或柠檬酸。
  15. 根据权利要求14所述的方法，其特征在于，所述式(I)化合物与所述酸的投料摩尔比为1∶1～2。
  16. 根据权利要求14所述的方法，其特征在于，所述的溶剂为选自醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚，脂肪烃类溶剂中的一种或多种的组合。
  17. 根据权利要求16所述的方法，其特征在于，所述的溶剂为选自乙腈、乙酸乙酯、丙酮、四氢呋喃中的一种或多种的组合。
  18. 根据权利要求14所述的方法，其特征在于，所述的反应温度为0～40℃。
  19. 一种药物组合物，包括活性成分和药学上可接受的载体，其特征在于，所述的活性成分为如权利要求1至13中任一项所述的式(I)化合物的盐。
  20. 如权利要求1至13中任一项所述的式(I)化合物的盐在制备治疗癌症药物中的用途。
PCT/CN2016/072729 2015-01-29 2016-01-29 (3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法 WO2016119742A1 (zh)

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