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WO2018019188A1 - Polymorphe de promédicament de nucléoside phosphoramidate et son procédé de préparation - Google Patents

Polymorphe de promédicament de nucléoside phosphoramidate et son procédé de préparation Download PDF

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Publication number
WO2018019188A1
WO2018019188A1 PCT/CN2017/093925 CN2017093925W WO2018019188A1 WO 2018019188 A1 WO2018019188 A1 WO 2018019188A1 CN 2017093925 W CN2017093925 W CN 2017093925W WO 2018019188 A1 WO2018019188 A1 WO 2018019188A1
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Prior art keywords
solvent
compound
formula
crystal form
organic solvent
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English (en)
Chinese (zh)
Inventor
袁建栋
顾家宁
黄仰青
缪琳峰
梁朝华
孙占莉
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Brightgene Bio Medical Technology Co Ltd
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Brightgene Bio Medical Technology Co Ltd
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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 relates to the field of medical technology. More specifically, the present invention relates to a polymorph of a nucleoside phosphoramidate prodrug and a process for the preparation thereof. The invention further relates to a pharmaceutical composition comprising a polymorph of a nucleoside phosphoramidate prodrug and at least one pharmaceutically acceptable carrier and the use of said pharmaceutical composition.
  • NUC-1031 is a gemcitabine prodrug developed by NuCana BioMed and currently in clinical phase III for the treatment of advanced solid tumors, pancreatic cancer, breast cancer and other cancers.
  • the CAS of NUC-1031 is 840506-29-8 and has the structure shown in the following formula:
  • Compound I is a NUC-1031 chiral P which is an S epimer, which has a CAS of 1562406-27-2 and has the following structure:
  • WO2014076490A1 discloses the following method for preparing NUC-1031,
  • the present inventors have found through a large amount of research work that Compound I exhibits relatively strong cytotoxicity against BxPC-3, MIA Paca-2 and OVCAR-3 tumor cells compared with NUC-1031, and the IC 50 value is about 0.01. Between nM and 0.05 nM; its inhibitory effect on tumor cell proliferation in vitro is about 10 times that of NUC-1031 chiral P in the R configuration; pharmacokinetic evaluation results show that compound I is active in tumor tissue. The product dFdCTP concentration was significantly higher than that of the NUC-1031 chiral P in the R configuration. Thus, there is a great difficulty in preparing a dosage form for an effective therapeutic dose, and the industrial expansion of production costs is very high.
  • NUC-1031 is very lipophilic, so it is difficult to dissolve in water (calculated solubility ⁇ 0.1mg/mL), and the pH range of the pKas estimated by its ionic part is not suitable for parenteral administration.
  • the S-epimer (Compound I) was found to have good solubility in a mixed solution of a plurality of polar organic solvents and water, and is suitable for preparation of a preparation. It is of great significance to develop a compound I with a stable crystalline form to meet the needs of the formulation and clinical needs.
  • the present invention provides a crystal form A of a compound of the formula I.
  • a second aspect of the invention provides the use of Form A for the manufacture of a medicament for the treatment and/or prevention of cancer.
  • a third aspect of the invention provides a pharmaceutical composition comprising Form A of the invention and at least one pharmaceutically acceptable excipient.
  • a fourth aspect of the invention provides a process for the preparation of a crystalline form A of a compound of formula I.
  • the invention provides a crystalline form A of a compound of the formula I, characterized in that the crystal form A has an X-ray powder diffraction (XRPD) pattern having a peak at least at the following 2 theta angle: 6.9 ⁇ 0.2 , 13.9. ⁇ 0.2, 20.8 ⁇ 0.2, and 21.1 ⁇ 0.2,
  • XRPD X-ray powder diffraction
  • the Form A has an X-ray powder diffraction (XRPD) pattern having peaks at least at the following 2 theta angles: 6.9 ⁇ 0.2, 13.9. ⁇ 0.2, 18.4 ⁇ 0.2, 18.8 ⁇ 0.2, 20.8 ⁇ 0.2, and 21.1 ⁇ 0.2. .
  • XRPD X-ray powder diffraction
  • the crystal form A having an X-ray powder diffraction (XRPD) pattern is substantially as shown in FIG. 1, FIG. 3, FIG. 4, or FIG.
  • Another aspect of the invention also provides the use of Compound I having Form A for the manufacture of a medicament for the treatment and/or prevention of cancer.
  • the cancer includes, but is not limited to, pancreatic cancer, advanced solid tumor, ovarian tumor, non-small cell lung cancer, breast cancer, bladder cancer, cervical cancer, mesothelioma, esophageal cancer, gastric cancer, colon cancer, liver cancer, cholangiocarcinoma, nasal Pharyngeal cancer, testicular cancer, lymphoma or head and neck cancer.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form A of the present invention together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be administered orally or parenterally, including intravenous, subcutaneous, intraperitoneal, intramuscular, inhalation, rectal, and topical (such as oral or sublingual). Administration).
  • the pharmaceutical composition for oral administration includes a tablet, a capsule, a granule or a suspension; the tablet for oral administration comprises the composition provided by the present invention as an active ingredient, and may further comprise one or more Pharmaceutically acceptable excipients such as diluents, disintegrating agents, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives.
  • suitable inert diluents include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate and lactose.
  • the binder comprises starch and gelatin.
  • the lubricant is magnesium stearate, stearic acid or talc.
  • the tablet may also be coated with glyceryl monostearate or glyceryl distearate to delay absorption in the stomach.
  • Capsules for oral administration include hard capsules and soft capsules, wherein the hard capsules comprise the composition provided by the present invention as an effective active ingredient and a solid diluent; the soft capsules comprise the pharmaceutical composition provided by the present invention as an effective active ingredient With water or oil (such as peanut oil, liquid paraffin or olive oil).
  • water or oil such as peanut oil, liquid paraffin or olive oil.
  • a dosage form of a suppository for rectal administration wherein the base of the suppository may be cocoa butter or a salicylate.
  • Formulations for vaginal administration are in the form of pessaries, cotton balls, creams, gels, pastes, foams, or sprays, which comprise compositions containing active ingredients and conventional carriers known in the art.
  • compositions provided herein are typically sterile solutions or sterile suspensions, and have suitable pH and osmotic pressure.
  • the preparation of such formulations can be prepared according to conventional methods well known in the art.
  • a fourth aspect of the invention provides a process for the preparation of a crystalline form A of a compound of formula I, the process comprising the steps of:
  • the first organic solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, and a mixed solution thereof; more preferably, the first organic solvent is selected from ethyl acetate.
  • the second organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, and a mixed solution thereof; more preferably, the second organic solvent is selected from the group consisting of methanol.
  • the ratio of the first solvent to the second solvent is from 6:1 to 20:1 (v/v), more preferably from 6:1 to 15:1 (v/v), still more preferably 8:1. ⁇ 12:1.
  • the total solvent amount ratio of the compound of the formula I to the first solvent and the second solvent is from 1:5 to 1:40 (w/v); preferably, the formula I
  • the total solvent ratio of the compound to the first solvent and the second solvent is 1:10-1:30 (w/v); more preferably, the compound of the formula I is combined with the first solvent and the second solvent.
  • the total solvent usage ratio is 1:15-1:25 (w/v).
  • the mixture I is stirred and heated to 20 ° C to 80 ° C, preferably to 60 ° C ⁇ 10 ° C, and then a second organic solvent is added, and the solid is dissolved and then filtered hot to obtain a filtrate. II.
  • the filtrate II was cooled to room temperature, stirred and crystallized, and then filtered, and the filter cake was washed with a first organic solvent and dried to obtain a crystal form A.
  • the method for preparing the crystal A of the compound of the formula I according to the present invention is as follows: ethyl acetate, a compound of the formula I is added to the reaction flask, the temperature is raised to 60 ⁇ 2 ° C, and methanol is added thereto, and the solid is dissolved. Hot filtration.
  • the filtrate is slowly cooled to 25 ⁇ 2 ° C, stirred for 2 to 24 hours, preferably 4-12 hours, more preferably 6-8 hours, then filtered, the filter cake is rinsed with ethyl acetate, and the filter cake is at 25 ⁇ 5 ° C Drying in vacuo to obtain Form A, wherein the ratio of the weight of the compound of Formula I to the total amount of ethyl acetate and methanol is 1:15 to 25 (w/v), and the ratio of ethyl acetate to methanol is 8-12. :1(v/v).
  • the compound I of the crystalline form A provided by the present invention is in a substantially pure crystalline form.
  • the crystalline form is characterized by being free or substantially free of water.
  • the invention provides a novel crystal form of the compound I, that is, the crystal form A, and the crystal form A provided by the invention has good stability and high purity, is suitable for preparing various preparations, and provides the crystal form A.
  • the preparation method is simple, the solvent used is a conventional solvent, no special equipment is required, the industrial production cost is small, and the purity of the crystal form A prepared by the method provided by the invention is remarkably improved.
  • Figure 1 shows an XRPD (X-ray powder diffraction) pattern of Form A of the compound of Formula I prepared in Example 1; wherein the diffraction peak data is as follows:
  • Fig. 2 is a view showing three samples which were respectively determined by an X-ray powder diffractometer after being taken out after 3 months, 6 months, and 12 months in the stability study experiment of the crystal form A in Example 27.
  • Figure 3 is an XRPD pattern of Form A taken in Example 27 for 3 months.
  • Figure 4 is an XRPD pattern of Form A taken in Example 27 for 6 months.
  • Figure 5 is an XRPD pattern of Form A taken in Example 27 for 12 months.
  • the content of the present invention is further illustrated and described in conjunction with the embodiments, which are intended to illustrate the invention and not to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, unless otherwise stated Or the number of parts by weight.
  • the compound of the formula I (abbreviated as the compound I) used in the present invention can be obtained by the method disclosed in WO2016055769, or can be obtained by the method disclosed in the patent application No. 201510586447.6, and the HPLC purity of the compound I used is above 95%. .
  • the XRPD test in the present invention uses a PAERT-type XPERT-3 X-ray diffractometer from PANalytical. Approximately 10 mg of the sample was evenly spread on a single crystal silicon sample pan and subjected to XRPD testing using the parameters described below.
  • Example 1 Referring to the preparation method of Example 1, using ethyl acetate as the first solvent and methanol as the second organic solvent, the temperature of the mixture of ethyl acetate and compound I in Example 1 was replaced with different temperatures, and the experimental results were obtained.
  • the effect is as follows:
  • the first organic solvent and the compound I were added to a 2 L reaction flask, and the mixture was heated to 60 ⁇ 10 ° C with stirring, and a second organic solvent was added thereto. The solid was dissolved and then filtered. The filtrate was slowly cooled to 25 ⁇ 5 ° C, stirred for 4 to 12 hours, filtered, using the first The filter cake is rinsed with an organic solvent, and the filter cake is dried under vacuum at 25 ⁇ 5° C., wherein the ratio of the first solvent to the second solvent is 8:1 to 12:1 (v/v), and the compound I and the two solvents are used. The total dosage ratio is 1:15 to 25 (w/v).
  • the experimental results are as follows:
  • HPLC content and related substance analysis selected methanol-water as solvent, GC residual solvent selected N, N-dimethylformamide as solvent, and the compound I crystal form A of the present invention was investigated in the solvent methanol, ethanol, N, N-di Solubility in methylformamide, ethyl acetate, water, 0.1 mol/L hydrochloric acid, and 0.1 mol/L sodium hydroxide.
  • the solubility of this product is set to: soluble in methanol, in N It is easily soluble in N-dimethylformamide, slightly soluble in ethanol, very slightly soluble in ethyl acetate, and almost insoluble in water.
  • Compound I crystal form A three batches of laboratory batch (batch 150801, 150901, S151001) and three batches of amplified batch (batch: S151201, S160101, S160102) in methanol, N, N-dimethylformamide, ethanol, acetic acid
  • the solubility results for ethyl ester and water are shown in the table below.
  • the compound I of the present invention When the compound I of the present invention is used in clinical practice, it is usually required to be an injection or a lyophilized powder.
  • the solubility of the compound I is very significant for the preparation of such a preparation, and it is apparent from the comparison of Table 5 and Table 6,
  • the solubility of Form A provided by the present invention is significantly better than that of WO2016055769A1. Therefore, the Form A of Compound I provided by the present invention will be more advantageous for the research and development of subsequent preparations.
  • Example 27 Using XRPD to study whether crystal form A provided by the present invention undergoes crystal transformation:
  • the crystal form A prepared according to the method of Example 1 was separately placed in a closed container and placed at 25 ° C ⁇ 2 ° C, 60% ⁇ 10% RH, and taken out after 3 months, 6 months, and 12 months, respectively.
  • the measurement is carried out by using an X-ray powder diffractometer, and the measurement results are as shown in FIGS. 2 to 5, wherein FIG. 2 is a comparison chart of three measurement times, and FIG. 3 is an XRPD chart measured for 3 months. 4 is the XRPD pattern measured for 6 months, and FIG. 5 is the XRPD pattern measured for 12 months.
  • the XRPD test in this example used a PANalytical XPERT-3 type X-ray diffractometer. Approximately 10 mg of the sample was evenly spread on a single crystal silicon sample pan and subjected to XRPD testing using the parameters described below.
  • the crystal form of the present invention is a more stable crystal form, and the XRPD test is carried out at 25 ° C for 12 months without crystal transformation, and the crystal form disclosed in the patent document (WO2016055769A1) is placed for a long time. Partial crystal transformation occurred.
  • Example 28 Comparison of the stability of different crystal forms by HPLC:
  • crystal forms disclosed in the crystal form A and the patent document (WO2016055769A1) prepared according to the method of the first embodiment of the present invention are respectively placed in a closed container and placed at 5 ° C ⁇ 3 ° C, respectively, at 0 days, 3 months, 6 After 9 months, take out the purity measurement after 9 months.
  • HPLC test conditions were as follows: high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512), silica gel column (YMC-hydrosphere C18, 150mm ⁇ 4.6mm, 3 ⁇ m or equivalent performance column); 0.1% phosphoric acid solution Mobile phase A with methanol-acetonitrile (30:70) as mobile phase B; flow rate of 1.0 ml per minute; column temperature of 25 ° C; detection wavelength of 220 nm. The results of the measurements are shown in the stability test comparison results in the table below.
  • the crystal form A long-term stability ratio of the present invention has a significant advantage over the crystal form disclosed in WO2016055769A1.
  • the crystal form A of the present invention and the patent document (WO2016055769A1) provide a small difference in the wettability of the crystal form, and the raw materials of the two crystal forms have no or almost no hygroscopicity.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une forme cristalline A d'un promédicament de phosphoramidate de nucléoside tel que présenté dans la formule I et un procédé de préparation associé. La forme cristalline A présente au moins une diffraction des rayons X sur poudre (XRPD) avec des pics aux angles 2θ de 6.9 ± 0.2°, 13.9 ± 0.2°, 20.8 ± 0.2° et 21.1 ± 0.2°. La forme cristalline A est de nature stable et appropriée pour être préparée en diverses formes posologiques. Le procédé de préparation est simple à utiliser, et la forme cristalline préparée A est de haute pureté et présente un faible coût d'industrialisation.
PCT/CN2017/093925 2016-07-23 2017-07-21 Polymorphe de promédicament de nucléoside phosphoramidate et son procédé de préparation Ceased WO2018019188A1 (fr)

Applications Claiming Priority (2)

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CN201610583741.6 2016-07-23
CN201610583741 2016-07-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369757A (zh) * 2018-11-12 2019-02-22 浙江外国语学院 一种制备索非布韦晶型6的方法
CN113698405A (zh) * 2021-06-03 2021-11-26 南方科技大学坪山生物医药研究院 一种核苷类化合物的晶型及其制备方法
US11377467B2 (en) 2015-12-23 2022-07-05 NuCana plc Crystalline form of gemcitabine
US12227567B2 (en) 2017-07-25 2025-02-18 Truebinding, Inc. Treating cancer by blocking the interaction of TIM-3 and its ligand

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114539338A (zh) * 2022-01-05 2022-05-27 苏州赜文医药科技有限公司 一种三磷酸腺苷二钠的三水合物晶体及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014076490A1 (fr) * 2012-11-16 2014-05-22 University College Cardiff Consultants Limited Procédé de préparation de promédicaments à base de nucléosides
WO2015198058A1 (fr) * 2014-06-25 2015-12-30 Nucana Biomed Limited Promédicaments de gemcitabine
WO2016055769A1 (fr) * 2014-10-06 2016-04-14 Nucana Biomed Limited Procédés de séparation de diastéréoisomères de gemcitabine-phosphate
CN106539810A (zh) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 一种富集了nuc-1031单一异构体的组合物及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014076490A1 (fr) * 2012-11-16 2014-05-22 University College Cardiff Consultants Limited Procédé de préparation de promédicaments à base de nucléosides
WO2015198058A1 (fr) * 2014-06-25 2015-12-30 Nucana Biomed Limited Promédicaments de gemcitabine
WO2016055769A1 (fr) * 2014-10-06 2016-04-14 Nucana Biomed Limited Procédés de séparation de diastéréoisomères de gemcitabine-phosphate
CN106539810A (zh) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 一种富集了nuc-1031单一异构体的组合物及其制备方法和用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11377467B2 (en) 2015-12-23 2022-07-05 NuCana plc Crystalline form of gemcitabine
US12227567B2 (en) 2017-07-25 2025-02-18 Truebinding, Inc. Treating cancer by blocking the interaction of TIM-3 and its ligand
CN109369757A (zh) * 2018-11-12 2019-02-22 浙江外国语学院 一种制备索非布韦晶型6的方法
CN109369757B (zh) * 2018-11-12 2020-12-29 浙江外国语学院 一种制备索非布韦晶型6的方法
CN113698405A (zh) * 2021-06-03 2021-11-26 南方科技大学坪山生物医药研究院 一种核苷类化合物的晶型及其制备方法

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