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WO2018177276A1 - Forme cristalline d'inhibiteur de tubuline - Google Patents

Forme cristalline d'inhibiteur de tubuline Download PDF

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Publication number
WO2018177276A1
WO2018177276A1 PCT/CN2018/080617 CN2018080617W WO2018177276A1 WO 2018177276 A1 WO2018177276 A1 WO 2018177276A1 CN 2018080617 W CN2018080617 W CN 2018080617W WO 2018177276 A1 WO2018177276 A1 WO 2018177276A1
Authority
WO
WIPO (PCT)
Prior art keywords
butyl
methylene
dione
fluorophenyl
tert
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/CN2018/080617
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English (en)
Chinese (zh)
Inventor
唐田
彭江华
靳如意
杨经安
佘琴
石涛
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.)
Shenzhen Neptunus Pharmaceutical Research Institute Co Ltd
Original Assignee
Shenzhen Neptunus Pharmaceutical Research Institute 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.)
Filing date
Publication date
Application filed by Shenzhen Neptunus Pharmaceutical Research Institute Co Ltd filed Critical Shenzhen Neptunus Pharmaceutical Research Institute Co Ltd
Publication of WO2018177276A1 publication Critical patent/WO2018177276A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • the invention belongs to the technical field of medicine, in particular to a new crystal form of a tubulin inhibitor.
  • anti-tumor drugs have made considerable contributions to prolonging the survival time of patients and improving their quality of life.
  • drugs acting on microtubules have a very important position in oncology drugs.
  • the current clinical drugs are affected by the following unfavorable problems: poor water solubility, unfavorable drug administration, and easy to cause allergic reactions, serious toxic side effects, and acquired drug resistance, resulting in reduced efficacy, complicated chemical structure, and difficulty in synthesis.
  • the sources are scarce, limiting their further use.
  • Chinese patent application CN106565686A discloses a novel small molecule tubulin inhibitor of simple structure. Since the drug molecules of different crystal forms have significant differences in solubility, melting point, dissolution rate, bioavailability, etc., preparation of a drug crystal form having a certain melting point, good chemical stability, high temperature resistance, etc. will be beneficial to the drug. Preparation and application of the formulation.
  • VDA-1 has the structure shown in formula (I):
  • Form A of the VDA-1 are characterized by melting point, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and infrared spectroscopy (IR).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • IR infrared spectroscopy
  • the A crystal form when X-ray powder diffraction is performed with a Cu radiation source, the A crystal form includes characteristic diffraction peaks at 6.6 ⁇ 0.2, 9.7 ⁇ 0.2, and 16.0 ⁇ 0.2 (°) at 2 ⁇ , and the relative of these peaks The intensity (I/I 0 ) is greater than or equal to 30%. Further, the crystal may further comprise, in X-ray powder diffraction, at 13.4 ⁇ 0.2, 16.3 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 25.5 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 at 2 ⁇ . Characteristic diffraction peaks of ⁇ 0.2 (°), the relative intensities of these peaks are all greater than or equal to 16% (see Figure 1). Where " ⁇ 0.2°" is the allowable measurement error range.
  • the Form A of the present invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has the characteristic peak represented by the above 2 ⁇ , as shown in Table 1, and its relative intensity is close to the following values.
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions.
  • the relative intensity value may be a value within a certain range, preferably a range selected from the range of ⁇ 25% of the value shown in Table 1, and more preferably a range of ⁇ 10% of the value shown in Table 1.
  • the above A crystal form has the X-ray powder diffraction pattern shown in Fig. 1.
  • the present invention characterizes the Form A of VDA-1 using differential scanning calorimetry (DSC) techniques (see Figure 2), wherein the maximum endotherm with differential scanning calorimetry is 146.5 °C.
  • DSC differential scanning calorimetry
  • the invention uses thermogravimetric analysis technology to characterize the crystal form of VDA-1 (see Fig. 3), wherein the thermogravimetric diagram (TG) shows a weight loss of 1.0% at 127.1 °C, indicating that the adsorbed water is lost at this temperature. . The weight loss at 235.9 ° C exceeded 16%, indicating that the compound degraded as the temperature increased.
  • Another object of the present invention is to provide a process for the preparation of VDA-1 Form A.
  • a final object of the present invention is to provide the use of VDA-1 Form A for the preparation of a medicament for the treatment of hyperproliferative diseases.
  • the crude product of VDA-1 is first prepared, and then the crude material is crystallized by the recrystallization method of the present invention to obtain a new crystal form, and the melting point measurement, X-ray is performed on the crystal.
  • a process for preparing the VDA-1A crystalline form comprises: adding a crude VDA-1 to ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide and tetrahydrofuran In a mixed solvent or added to a mixed solvent of C3-C4 alkyl ketone and tetrahydrofuran, heated to reflux until dissolved; after the solution is clarified, the temperature is lowered to precipitate a solid, and the solid is collected by filtration, and the collected solid is air-dried to obtain A crystal. type.
  • the ketone is selected from the group consisting of acetone, methyl ethyl ketone and n-butyl ketone, etc., a preferred solvent mixture of ethyl acetate and tetrahydrofuran, a mixed solvent of acetone and tetrahydrofuran; ethyl acetate, dimethyl sulfoxide, N, N - the volume ratio (V / V) of dimethylformamide, ketone and tetrahydrofuran is 1:1 to 1:5; the ratio of the crude product to the solvent is 1 (g) by weight to volume ratio (W/V). : 5 to 30 (ml), preferably 1:10 (g/ml).
  • the solution is preferably heated to 50 to 80 ° C, more preferably ethyl acetate, a mixed solvent of a C3-C4 alkyl ketone and a tetrahydrofuran, and heated to 60 ° C; according to this embodiment, the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 5 to 15 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 45 ° C.
  • a pharmaceutical composition comprising Form A of Form V of the present invention, the pharmaceutical composition comprising the novel crystalline form compound and optionally a pharmaceutically acceptable carrier and/or form Agent.
  • the pharmaceutical composition can be further formulated into a form for administration according to a conventional formulation method, including an oral or parenteral administration form.
  • a therapeutically effective amount of Form A of VDA-1 should be included.
  • therapeutically effective amount is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.
  • the A crystal form of VDA-1 can be used alone for the preparation of a medicament for treating a proliferative disease, or can be prepared in combination with other therapeutic agents to synergistically.
  • the present invention produces (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-(( E)-3-(3-fluorophenyl)-2-propenylene)piperazin-2,5-dione (VDA-1) Form A, which has a stable morphology and a defined melting point, chemically stable Good in properties and high in temperature resistance, the A crystal form of VDA-1 has the properties required for preparation of the preparation, and is convenient to store, simple in production operation, and easier to control in quality.
  • the crystalline form A of VDA-1 of the present invention is for treating a hyperproliferative disease.
  • the hyperproliferative disease is cancer, including but not limited to non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer. , pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or neck cancer.
  • Figure 1 is an X-ray diffraction pattern of Form A of VDA-1;
  • Figure 2 is a DSC pattern of Form A of VDA-1
  • Figure 3 is a TG map of Form A of VDA-1
  • Figure 4 is an IR spectrum of Form A of VDA-1
  • Figure 5 is an HPLC chromatogram of Form A of VDA-1.
  • the preparation method of the crude VDA-1 includes the steps (1) to (3):
  • Example 2.1 The method according to Example 2.1, wherein the solvent, the heating temperature, the precipitation temperature and time, and the drying temperature are as shown in Table 2, respectively.
  • Example 2.9 and 2.11 had high solvent residues, which affected the quality.
  • the sample of Example 2.10 was hygroscopic and was also a challenge to the formulation process.
  • the crystalline form obtained in Example 2.1, the VDA-1A crystalline form is the predominant crystalline form.
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2 ⁇ range: 3° to 50°, step size 0.02 °, each step of stay time 40S.
  • Test basis People's Republic of China (2015 edition four) 0451 X-ray powder diffraction method
  • Test sample quality Sample 1: 2.48mg (using aluminum sample tray)
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • thermogravimetric analyzer
  • Test conditions atmosphere: air, 20ml / min;
  • Test basis General rules for thermal analysis JY/T 014-1996
  • Test basis GB/T 6040-2002 General rules for infrared spectrum analysis
  • Mobile phase A water-mobile phase acetonitrile B (80:20)
  • Test basis "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography
  • Example 2.1 The stability of the crystal form A obtained in Example 2.1 was examined (10-day accelerated test), and the crystal form A was placed at 60 ° C, humidity of 92.5%, and light conditions, and the results are shown in the following table.
  • VDA-1 crystal form A Take the prescribed amount of polysorbate-80, while stirring, add VDA-1 crystal form A, stir to dissolve VDA-1, and pass the solution through a microfiltration membrane for positive pressure filtration until the solution is clear, the determined content is 98.36. % and pH are 6.14. After passing the test, the solution is filled in an antibiotic-controlled bottle in a clean condition, 0.5 ml (including VDA-1) per bottle, and the rubber stopper and aluminum cover are obtained.
  • the prepared injection was allowed to stand at 40 ° C for 7 days and 0 days, and the effect of the addition of acid and the addition of different acids, and the different processes of the same formulation, such as nitrogen and no nitrogen, on the stability of the injection of Form A were compared.
  • Y2 indicates the standard colorimetric liquid yellow No. 2 (in accordance with the Chinese Pharmacopoeia 2015 edition, supervised by Shanghai Pharmaceutical Inspection Institute)
  • Example 5.3 no acid is added in Example 5.3. After 7 days at 40 °C, the related substances are significantly increased, the VDA-1 content is decreased, and other indexes are not significantly changed. 13% hydrochloric acid (Example 5.2) or 50% citric acid is added (implementation)
  • the prescription of Example 5.4) is significantly better than the prescription without acid (Example 5.3), while the prescription for adjusting the pH with 13% hydrochloric acid is superior to the prescription for adjusting the pH with 50% citric acid.
  • the same prescription process is different, such as implementation.
  • the content of nitrogen-passing sample and the related substances did not change much after being placed at 40 °C for 7 days.
  • the content of nitrogen-free samples decreased and the related substances increased significantly.
  • the stability of nitrogen-passing samples was better than that of nitrogen-free samples.
  • 5.1 is the formulation and preparation process of VDA-1 injection (through nitrogen).

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

Abstract

La présente invention concerne une forme cristalline de (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazol-4-yl)méthylène]-6-((E)-3-(3-fluorophényl)-2-propénylidène)pipérazine -2,5-dione (VDA -1). La forme cristalline A présente une morphologie stable, un point de fusion précis, et une bonne stabilité chimique et est résistante à haute température et appropriée pour des utilisations pharmaceutiques. La forme cristalline A peut être utilisée pour traiter une maladie hyperproliférative.
PCT/CN2018/080617 2017-03-31 2018-03-27 Forme cristalline d'inhibiteur de tubuline Ceased WO2018177276A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710208171.7A CN108658945B (zh) 2017-03-31 2017-03-31 一种微管蛋白抑制剂（vda-1）的a晶型
CN201710208171.7 2017-03-31

Publications (1)

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WO2018177276A1 true WO2018177276A1 (fr) 2018-10-04

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WO (1) WO2018177276A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019149254A1 (fr) * 2018-02-01 2019-08-08 深圳海王医药科技研究院有限公司 Forme cristalline d'un composé immunitaire à petites molécules, son procédé de préparation et composition pharmaceutique la contenant

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054498A2 (fr) * 2002-08-02 2004-07-01 Nereus Pharmaceuticals, Inc. Deshydrophenylahistines et analogues de ceux-ci et synthese de ces deshydrophenylahistines et d'analogues de ceux-ci
CN1934101A (zh) * 2004-02-04 2007-03-21 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
CN106565686A (zh) * 2016-10-11 2017-04-19 深圳海王医药科技研究院有限公司 微管蛋白抑制剂

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1926724A1 (fr) * 2005-09-21 2008-06-04 Nereus Pharmaceuticals, Inc. Analogues de deshydrophenylahistines et utilisation therapeutique de ceux-ci
WO2012035436A1 (fr) * 2010-09-15 2012-03-22 Tokyo University Of Pharmacy And Life Sciences Analogues de promédicaments à base de plinabuline et utilisations thérapeutiques associées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054498A2 (fr) * 2002-08-02 2004-07-01 Nereus Pharmaceuticals, Inc. Deshydrophenylahistines et analogues de ceux-ci et synthese de ces deshydrophenylahistines et d'analogues de ceux-ci
CN1934101A (zh) * 2004-02-04 2007-03-21 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
CN106565686A (zh) * 2016-10-11 2017-04-19 深圳海王医药科技研究院有限公司 微管蛋白抑制剂

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019149254A1 (fr) * 2018-02-01 2019-08-08 深圳海王医药科技研究院有限公司 Forme cristalline d'un composé immunitaire à petites molécules, son procédé de préparation et composition pharmaceutique la contenant

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CN108658945A (zh) 2018-10-16
CN108658945B (zh) 2020-11-20

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