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WO2017121379A1 - Sel de p-toluènesulfonate pour réguler un composé kinase, et cristaux correspondants - Google Patents

Sel de p-toluènesulfonate pour réguler un composé kinase, et cristaux correspondants Download PDF

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Publication number
WO2017121379A1
WO2017121379A1 PCT/CN2017/071102 CN2017071102W WO2017121379A1 WO 2017121379 A1 WO2017121379 A1 WO 2017121379A1 CN 2017071102 W CN2017071102 W CN 2017071102W WO 2017121379 A1 WO2017121379 A1 WO 2017121379A1
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WIPO (PCT)
Prior art keywords
compound
formula
crystal
benefit
crystallization
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/071102
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English (en)
Chinese (zh)
Inventor
李继军
朱岩
王虎庭
韩永信
黄体聪
李新路
赵锐
张喜全
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Centaurus Biopharma Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Centaurus Biopharma Co Ltd
Priority to CN201780006076.7A priority Critical patent/CN108602824A/zh
Publication of WO2017121379A1 publication Critical patent/WO2017121379A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application belongs to the field of medicine, and relates to a p-toluenesulfonate and a crystal thereof for regulating a kinase compound, in particular, to N- ⁇ 3-[3-(9H- ⁇ -6-yl)pyridin-2-ylamino ]-4-Chloro-2-fluorophenyl ⁇ -3-fluoropropane-1-sulfonamide p-toluenesulfonate and its crystallization.
  • Example 9 of WO2013071865A1 discloses a kinase-regulating compound having the chemical name N- ⁇ 3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2 -Fluorophenyl ⁇ -3-fluoropropane-1-sulfonamide, the structure is as shown in Formula I:
  • Compound of Formula I as a free form is a kinase-modulating compound useful in the treatment of diseases and conditions associated with modulation of kinase activity.
  • the compounds of formula I have excellent anti-B-RAF enzyme activity in vitro and are useful in the treatment of diseases and conditions associated with modulation of B-RAF enzyme activity.
  • the application provides a compound of formula II,
  • the application provides crystallization of a compound of formula II,
  • the compound of formula II is crystallized using an X-ray powder diffraction pattern of Cu K ⁇ radiation, and the diffraction angle (2 ⁇ ⁇ 0.2°) has diffraction peaks at about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, and 20.78°. .
  • the present application provides a crystalline composition comprising a crystal of a compound of formula II as described herein, wherein the compound of formula II comprises more than 50% by weight of the crystalline composition, 80 More than %, more than 90%, more than 95% or more than 99%.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II as described herein or a crystalline form of said compound of formula II or a crystalline composition as described above, and one or A variety of pharmaceutically acceptable carriers.
  • the application provides a compound of formula II as described herein or a crystalline form of the compound of formula II or a crystalline composition as described above or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition the use of.
  • the present application also provides a compound of Formula II described herein or a compound of Formula II described herein or a crystalline composition thereof or a pharmaceutical composition as described above for use in the treatment of a protein kinase mediated disease or condition.
  • the present application also provides a method of treating a protein kinase mediated disease or condition, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula II as described herein or a crystal of said compound of formula II or a combination of said crystals Or the above pharmaceutical composition.
  • the present application provides a process for the preparation of a crystallization of a compound of formula II comprising crystallizing a compound of formula II in a C 1-4 alcohol solvent to provide a crystallization of the compound of formula II.
  • the application provides N- ⁇ 3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl ⁇ -3 as shown in Formula II -Fluoropropane-1-sulfonamide p-toluenesulfonate (hereinafter referred to as a compound of formula II):
  • the compounds of formula II provided herein are superior to the compounds of formula I or other salts of the compounds of formula I in at least one aspect, such as bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.
  • the application provides crystallization of a compound of formula II,
  • crystals of the compound of formula II are substantially free of water of crystallization and/or other solvents.
  • Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 14.75°, 16.73°, 17.35°, 18.52. There are diffraction peaks at °, 20.78°, 21.60°, 21.92°, and 25.36°.
  • Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35. There are diffraction peaks at °, 18.52, 18.98, 20.09, 20.78, 21.60, 21.92, 23.11, 24.30, 25.36, 26.08, 26.62, 27.41, 27.85 and 28.32.
  • the diffraction angle (2 ⁇ ⁇ 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35.
  • a typical example of crystallizing a compound of formula II of the present application using an X-ray powder diffraction (XRD) pattern of Cu Ka radiation has the following characteristics:
  • a typical example of a crystal of a compound of formula II of the present application has an X-ray powder diffraction (XRD) pattern substantially as shown in FIG.
  • a typical example of a crystal of a compound of formula II of the present application has an XRD pattern substantially as shown in FIG.
  • a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of the compound of Formula II of the present application has an onset temperature of about 260.5 ° C, specifically, a difference substantially as shown in FIG.
  • a scanning calorimetry (DSC) measurement chart is shown.
  • a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of a compound of Formula II of the present application has an onset temperature of about 258.8 °C, specifically, a difference substantially as shown in FIG.
  • a scanning calorimetry (DSC) measurement chart is shown.
  • the crystallization of the compound of the formula II of the present application includes not only the diffraction angle of the peak in the X-ray powder diffraction completely coincides with the above diffraction angle or the crystal of ⁇ 0.2°, but also the diffraction angle having a uniform error of ⁇ 0.2°. crystallization.
  • the present application provides a crystalline composition comprising the crystal of the compound of the above formula II, wherein the crystal of the compound of the formula II accounts for 50% or more, 80% or more, 90% or more by weight of the crystal composition. More than 95% or more than 99%.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II or a compound of Formula II, or a crystalline composition thereof, and one or more pharmaceutically acceptable carriers .
  • the pharmaceutical compositions of the present application can be prepared by crystallizing a compound of formula II or a compound of formula II or a combination of the above crystalline compositions with a suitable pharmaceutically acceptable carrier.
  • the application provides the use of a compound of formula II or a compound of formula II above, or a crystalline composition as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition, preferably in preparation thereof Use in a medicament for treating a B-raf kinase mediated disease or condition, such as a cancer, mediated by a protein kinase (including B-raf kinase).
  • the present application also provides a compound of formula II, or a crystalline composition of the above formula II, or a crystalline composition thereof, or a pharmaceutical composition as described above, for use in the treatment of a disease or condition mediated by a protein kinase, including a B-raf kinase.
  • a protein kinase including a B-raf kinase.
  • the disease or condition mediated by the protein kinase can be, for example, a cancer.
  • the present application also provides a method of treating a disease or condition mediated by a protein kinase, including B-raf kinase, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula II described herein or a formula thereof.
  • the compound II crystallizes or the above crystalline composition or the above pharmaceutical composition.
  • the disease or condition mediated by the protein kinase can be, for example, a cancer.
  • the protein kinase (including B-raf kinase) mediated diseases or conditions described in the present application are selected from the group consisting of melanoma, colorectal cancer, colon cancer, gastric cancer, pelvic cancer, esophageal cancer, brain cancer, testicular cancer, bone cancer, lymph Cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, ovarian cancer, liver cancer, kidney cancer, glioma, sarcoma, medullary thyroid carcinoma, carcinoid, small cell lung cancer, leukemia, neurofibromatosis, myelodysplastic syndrome , tumor angiogenesis, neuropathic pain, inflammatory pain, acute and chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, multiple infarct dementia, head Injury, spinal cord injury, Parkinson's disease, Alzheimer's disease, psoriasis, arthritis, osteoarthritis, fibrosis, r
  • the crystallization of the compound of formula II provided herein is at least one aspect superior to the compound of formula I or other salt of the compound of formula I in terms of bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.
  • the crystal of the compound of the formula II provided by the present application has excellent solubility parameters suitable for the preparation of the drug; has high stability, for example, has higher stability than other salts of the compound of the formula I (such as potassium salt); is not easily deliquescent, for example, the compound of the formula I, hydrochloric acid Salts and sulfates are easily deliquescent; their impurity content is easily controlled, for example, in the preparation, under the experimental conditions of conventional stability investigation.
  • the compound of formula II of the present application can be prepared by the following method: a compound of formula I and p-toluenesulfonic acid are salted in a solvent to provide a compound of formula II.
  • the crystallization of the compound of the formula II of the present application can be obtained by the following method: a compound of the formula I and p-toluenesulfonic acid are salted in a solvent to obtain a compound of the formula II; the compound of the formula II is crystallized in a C 1-4 alcohol solvent to give a compound of the formula II. crystallization.
  • a compound of formula I is added to p-toluenesulfonic acid in a solvent, stirred at room temperature or under heating to remove the solvent to give a compound of formula II; a compound of formula II in a C 1-4 alcoholic solvent at room temperature or under heating, for example, under reflux conditions
  • the solution is formed under the following conditions, and the compound of the formula II is crystallized by cooling to about 0 ° C to room temperature, and dried by filtration to obtain a crystal of the compound of the formula II. It is optional during the crystallization to mix the solution while slowly cooling, which may be shaking or stirring.
  • the solvent used for salt formation is one or more polar protic solvents including, but not limited to, acetonitrile, tetrahydrofuran, ethyl acetate, methyl acetate, methyl formate, acetone or methyl ethyl ketone. .
  • the solvent used to form the salt is tetrahydrofuran.
  • the molar ratio of the compound of the formula I to p-toluenesulfonic acid is from 1:1-5, preferably from 1:1 to 2.
  • the C 1-4 alcohol solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol or tert-butanol, preferably methanol or ethanol. Or one or more of isopropanol, most preferably one or both of methanol or ethanol.
  • Patient means a mammal, preferably a human.
  • “Pharmaceutically acceptable” is those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without undue Toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • Treatment means administration of a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • Incident light path divergence slit 1°, anti-scatter slit 2°;
  • test method for the DSC pattern of the crystal of the above formula II of the present application is as follows:
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to the crystal.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • Figure 1 is an X-ray powder diffraction pattern of the crystal of the compound of formula II prepared in Example 3.
  • DSC differential scanning calorimetry
  • DSC differential scanning calorimetry
  • the compound of formula I is prepared according to the method disclosed in Example 9 of WO2013071865A1.
  • the compound of the formula II prepared in Example 3 was crystallized for a strong light irradiation test (4500 LX), a high temperature test (60 ° C) and a high humidity test (92.5%).
  • the investigation time was 10 days, and the purity was sampled on the 0th day and the 10th day respectively.
  • the test results are shown in Table 1.
  • Example 3 The crystallization of the compound of the formula II prepared in Example 3 was subjected to a wettability test. Test conditions: 25 ° C ⁇ 1 ° C, RH80% ⁇ 2% constant temperature and humidity box for more than 24h.
  • a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) was taken and placed in a suitable 25 ° C ⁇ 1 ° C constant temperature dryer on the day before the test, and the weight (m 1 ) was accurately weighed.
  • the thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m 2 ).
  • the weighing bottle was opened and placed under the above constant temperature and humidity conditions for 24 hours with the cap, and the weighing cap was covered, and the weight (m 3 ) was accurately weighed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un sel de p-toluènesulfonate permettant de réguler un composé kinase, et ses cristaux, et en particulier un sel de N-{3-[3-(9H-purine-6-groupe)pyridine-2-groupe amino]-4-chlore-2-fluorophényl}-3-fluoropropane-1-sulfonamide p-toluènesulfonate et ses cristaux. Le sel et les cristaux correspondants selon la présente invention présentent des avantages en termes de biodisponibilité, d'hygroscopie, de stabilité, de solubilité, de pureté, de facilité de préparation, et autres.
PCT/CN2017/071102 2016-01-15 2017-01-13 Sel de p-toluènesulfonate pour réguler un composé kinase, et cristaux correspondants Ceased WO2017121379A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780006076.7A CN108602824A (zh) 2016-01-15 2017-01-13 一种调节激酶化合物的对甲苯磺酸盐及其结晶

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610028119.9 2016-01-15
CN201610028119 2016-01-15

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WO2017121379A1 true WO2017121379A1 (fr) 2017-07-20

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CN (1) CN108602824A (fr)
TW (1) TW201726677A (fr)
WO (1) WO2017121379A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103102349A (zh) * 2011-11-14 2013-05-15 北京赛林泰医药技术有限公司 蛋白激酶抑制剂及其组合物和用途
CN103339132A (zh) * 2010-12-02 2013-10-02 友爱有限公司 新的嘌呤基吡啶基氨基-2,4-二氟苯基磺酰胺衍生物、其药学上可接受的盐、其制备方法及包含其作为活性成分的对Raf激酶具有抑制活性的药物组合物
CN103974954A (zh) * 2011-11-14 2014-08-06 北京赛林泰医药技术有限公司 调节激酶的化合物、含有它们的组合物及其用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103339132A (zh) * 2010-12-02 2013-10-02 友爱有限公司 新的嘌呤基吡啶基氨基-2,4-二氟苯基磺酰胺衍生物、其药学上可接受的盐、其制备方法及包含其作为活性成分的对Raf激酶具有抑制活性的药物组合物
CN103102349A (zh) * 2011-11-14 2013-05-15 北京赛林泰医药技术有限公司 蛋白激酶抑制剂及其组合物和用途
CN103974954A (zh) * 2011-11-14 2014-08-06 北京赛林泰医药技术有限公司 调节激酶的化合物、含有它们的组合物及其用途

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TW201726677A (zh) 2017-08-01

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