WO2016119742A1 - Sels de (3β)-17-(1h-benzimidazole-1-yl)androstane-5,16-diène-3-ol et leurs procédés de préparation - Google Patents

Sels de (3β)-17-(1h-benzimidazole-1-yl)androstane-5,16-diène-3-ol et leurs procédés de préparation 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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PCT/CN2016/072729
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English (en)
Chinese (zh)
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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.

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Abstract

La présente invention concerne des formes cristallines de phosphate, tartrate et citrate de (3β)-17-(1H-benzimidazole-1-yl)androstane-5,16-diène-3-ol et les procédés de préparation de ces derniers. Les formes cristallines de phosphate, tartrate et citrate d'un composé de formule (I) de la présente invention ont des caractéristiques avantageuses telles qu'une solubilité élevée, une faible hygroscopicité, une bonne stabilité, un processus de préparation simple, et, étant faciles à utiliser, sont appropriées pour le stockage et une production industrielle, et sont d'une valeur importante pour le développement et l'optimisation futures du médicament.
PCT/CN2016/072729 2015-01-29 2016-01-29 Sels de (3β)-17-(1h-benzimidazole-1-yl)androstane-5,16-diène-3-ol et leurs procédés de préparation WO2016119742A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018029223A1 (fr) * 2016-08-08 2018-02-15 Industriale Chimica S.R.L. Procédé de préparation de 3b-hydroxy-17-(1h-benzimidazol-1-yl) androsta -5,16-diène
IT201600121375A1 (it) * 2016-11-30 2018-05-30 Ind Chimica Srl PROCESSO PER LA PREPARAZIONE DI 3ß-IDROSSI-17-(1H-BENZIMIDAZOL-1-IL)ANDROSTA-5,16-DIENE
WO2024091899A1 (fr) * 2022-10-25 2024-05-02 University Of Maryland, Baltimore Sels de galétérone et de sels d'analogues de galétérone de nouvelle génération, et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091299A2 (fr) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Nouvelles polythérapies contre le cancer
WO2011017534A2 (fr) * 2009-08-07 2011-02-10 Tokai Pharmaceuticals, Inc. Traitement du cancer de la prostate
CN102822190A (zh) * 2009-11-13 2012-12-12 拓凯制药公司 哺乳动物的类固醇代谢物
WO2013096907A1 (fr) * 2011-12-22 2013-06-27 Tokai Pharmaceuticals, Inc. Méthodes et compositions pour la polythérapie à l'aide d'inhibiteurs de p13k/mtor
CN103813794A (zh) * 2011-07-18 2014-05-21 拓凯制药公司 用于治疗前列腺癌的新型组合物及方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2206719T3 (en) * 2005-03-02 2015-01-26 Univ Maryland A pharmaceutical composition comprising 3-BETA-HYDROXY-17- (1-H-benzimidazol-1-yl) androsta-5, 16-DIEN

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091299A2 (fr) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Nouvelles polythérapies contre le cancer
WO2011017534A2 (fr) * 2009-08-07 2011-02-10 Tokai Pharmaceuticals, Inc. Traitement du cancer de la prostate
CN102822190A (zh) * 2009-11-13 2012-12-12 拓凯制药公司 哺乳动物的类固醇代谢物
CN103813794A (zh) * 2011-07-18 2014-05-21 拓凯制药公司 用于治疗前列腺癌的新型组合物及方法
WO2013096907A1 (fr) * 2011-12-22 2013-06-27 Tokai Pharmaceuticals, Inc. Méthodes et compositions pour la polythérapie à l'aide d'inhibiteurs de p13k/mtor

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018029223A1 (fr) * 2016-08-08 2018-02-15 Industriale Chimica S.R.L. Procédé de préparation de 3b-hydroxy-17-(1h-benzimidazol-1-yl) androsta -5,16-diène
ES2700901R1 (es) * 2016-08-08 2019-03-04 Ind Chimica Srl Proceso para la preparación de 3ß-hidroxi-17-(1h-benzimidazol-1-il)androsta-5,16-dieno.
RU2749134C1 (ru) * 2016-08-08 2021-06-04 Индустриале Кимика С.Р.Л. СПОСОБ ПОЛУЧЕНИЯ 3β-ГИДРОКСИ-17-(1Н-БЕНЗИМИДАЗОЛ-1-ИЛ)АНДРОСТА-5,16-ДИЕНА
US11390645B2 (en) 2016-08-08 2022-07-19 Industriale Chimica S.R.L. Process for the preparation of 3β-hydroxy-17-(1H-benzimidazol-1-YL) androsta-5,16-diene
IT201600121375A1 (it) * 2016-11-30 2018-05-30 Ind Chimica Srl PROCESSO PER LA PREPARAZIONE DI 3ß-IDROSSI-17-(1H-BENZIMIDAZOL-1-IL)ANDROSTA-5,16-DIENE
WO2024091899A1 (fr) * 2022-10-25 2024-05-02 University Of Maryland, Baltimore Sels de galétérone et de sels d'analogues de galétérone de nouvelle génération, et leurs utilisations

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