WO2023098853A1 - Cocristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique - Google Patents

Cocristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique Download PDF

Info

Publication number
WO2023098853A1
WO2023098853A1 PCT/CN2022/136101 CN2022136101W WO2023098853A1 WO 2023098853 A1 WO2023098853 A1 WO 2023098853A1 CN 2022136101 W CN2022136101 W CN 2022136101W WO 2023098853 A1 WO2023098853 A1 WO 2023098853A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
cabozantinib
ratio
combined
xrpd
Prior art date
Application number
PCT/CN2022/136101
Other languages
English (en)
Chinese (zh)
Inventor
刘晓忠
郑和校
李郡
靳奇峰
Original Assignee
湖南湘源美东医药科技有限公司
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 湖南湘源美东医药科技有限公司 filed Critical 湖南湘源美东医药科技有限公司
Publication of WO2023098853A1 publication Critical patent/WO2023098853A1/fr

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4

Definitions

  • the present invention relates to a co-crystal formed by cabozantinib, a preparation method thereof and its application as a medicine or in a pharmaceutical preparation for the treatment of progressive, metastatic medullary thyroid cancer (MTC) patients, renal cancer and prostate cancer.
  • MTC metastatic medullary thyroid cancer
  • Cabozantinib is an anticancer drug developed by Exelixis. Its indications for the treatment of metastatic medullary thyroid carcinoma and kidney cancer were approved by the FDA in November 2012 and April 2016, respectively. In addition, Its indication for the treatment of liver cancer was also approved by the FDA in January 2019. Cabozantinib is marketed as (S)-malate.
  • the Chinese patent application CN102388024A of Exeli Axis Company discloses the 1:1 malate of cabozantinib.
  • WO2015177758 A1 discloses crystal form 1, crystal form 2, crystal form 3 and crystal form 4 of compound I, wherein crystal form 4 is a better crystal form, but this crystal form also has low solubility, fluidity, compressibility, The problem of poor tensile strength and adhesion. Therefore, a large number of experimental studies are still needed to provide more crystal forms and forms with better properties to support the development of drugs.
  • Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor, including nine targets of MET, VEGFR1 23, ROS1, RET, AXL, NTRK, and KIT.
  • cabozantinib The most common adverse reactions of cabozantinib included: diarrhea (63%), oral inflammation (51%), PPES or hand-foot syndrome (50%), weight loss (48%), decreased appetite (46%), nausea ( 43%), fatigue (41%), mouth pain (36%), hair color change (34%), taste disturbance (34%), high blood pressure (33%), constipation (27%), abdominal pain (27%) , vomiting (24%), weakness (21%), dysarthria (20%), rash (19%), dry skin (19%), headache (18%), hair loss (16%), dizziness (14%) , arthralgia (14%), dysphagia (13%), muscle cramps (12%), erythema (11%), dyspepsia (11%),
  • Grade 3-4 adverse reactions include: diarrhea (16%), PPES (hand-foot syndrome) (13%), fatigue (9%), hypertension (8%), weakness (6%), oral inflammation (5%) , weight loss (5%), decreased appetite (5%), dysphagia (4%), abdominal pain (3%), oral pain (2%), nausea (2%), dehydration (2%), erythema (1 %), hypotension (1%), rash (1%), arthralgia (1%), musculoskeletal chest pain (1%), nausea (1%).
  • the most common abnormal laboratory data in the cabozantinib group included: increased AST (86%), increased ALT (86%), decreased lymphocytes (53%), increased ALP (52%), hypocalcemia ( 52%), neutropenia (35%), thrombocytopenia (35%), hypophosphatemia (28%), hyperbilirubin (25%), hypomagnesemia (19%), hypokalemia hyperemia (18%), hyponatremia (10%).
  • the co-crystals of the present invention can meet one or more objectives such as but not limited to improved solubility, stability and bioavailability and better safety in pharmaceutical applications.
  • the present invention relates to the co-crystal of cabozantinib and gallic acid, DL-tartaric acid, maleic acid and piperazine.
  • the active substance is selected from cabozantinib
  • the co-crystal precursor is selected from gallic acid, DL-tartaric acid, maleic acid, piperazine.
  • co-crystals of the present invention are formed when cabozantinib (active pharmaceutical ingredient API) and gallic acid, DL-tartaric acid, maleic acid, piperazine (co-crystal precursor) are bound together by hydrogen bonding. In some embodiments, other non-covalent bonds and covalent interactions may also exist in the co-crystal.
  • One aspect of the invention contemplates cabozantinib-based co-crystals that provide sufficient levels of bioavailability to be therapeutically effective in pharmaceutical applications and to maintain levels for a therapeutically effective period of time.
  • the cabozantinib co-crystal designed in the present invention has better solubility and stability, is convenient for storage and use; and can be directly used for the preparation of solid preparations, and has good powder properties.
  • Figure 1 shows the X-ray powder diffraction (XRPD) pattern of cabozantinib and gallic acid co-crystal.
  • Figure 2 shows the X-ray powder diffraction (XRPD) patterns of cabozantinib and DL-tartaric acid co-crystals.
  • Figure 3 shows the X-ray powder diffraction (XRPD) patterns of cabozantinib and maleic acid co-crystals.
  • Figure 4 shows the X-ray powder diffraction (XRPD) pattern of cabozantinib and piperazine co-crystals.
  • Figure 5 shows the effect of cabozantinib co-crystals on the survival rate of medullary thyroid cancer cells.
  • Figure 6 shows the effect of cabozantinib co-crystal on the survival rate of renal cancer cell line 786-O.
  • Figure 7 shows the effect of cabozantinib co-crystal on the survival rate of prostate cancer cell PC-3.
  • the invention relates to a co-crystal of cabozantinib and a preparation method thereof.
  • the co-crystal contains cabozantinib and the co-crystal precursors gallic acid, DL-tartaric acid, maleic acid, piperazine.
  • cabozantinib and gallic acid are combined in a 1:1 ratio.
  • the co-crystal contained an X-ray diffraction pattern as shown in FIG. 1 .
  • the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 1 .
  • cabozantinib and DL-tartaric acid are combined in a 1:1 ratio.
  • the co-crystal has an XRPD pattern comprised of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° (rounded to 10.3°, 11.4°, 13.9°, 15.8 °, 17.9°, 20.6°, 23.0° and 27.9°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
  • the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 10.280°, 11.380°, 13.860°, 15.801°, 17.901°, 20.639°, 22.960°, and 27.881° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 2 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 2 .
  • cabozantinib and maleic acid co-crystal are combined in a 1:1 ratio.
  • the co-crystal had an XRPD pattern comprised of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381° and 25.359° (rounded to 7.0°, 8.8°, 10.2°, 11.9°, respectively , 13.9°, 17.5°, 23.4 and 25.4°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
  • the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381° and 25.359° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 6.999°, 8.760°, 10.159°, 11.919°, 13.939°, 17.460°, 23.381°, and 25.359° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 3 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 3 .
  • the cabozantinib and piperazine co-crystals are combined in a 1:2 ratio.
  • the co-crystal has an XRPD pattern.
  • the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 4 .
  • the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 4 .
  • the co-crystal of the present invention comprises: gallic acid, DL-tartaric acid, maleic acid, piperazine as co-former; and cabozantinib as co-former and active drug Ingredients (APIs).
  • cabozantinib and gallic acid, DL-tartaric acid, maleic acid are combined in a 1:1 ratio.
  • cabozantinib and maleic acid are combined in a 1:2 ratio.
  • the solid state of the co-crystal of the present invention is any crystalline polymorph or other mixture. Co-crystals can also be made in amorphous form, which can be combined with any crystalline form. In other embodiments, the solid state of the co-crystal is an amorphous form, different forms of the co-crystal of the present invention can be obtained by different crystallization processes, and the co-crystal can be made into an amorphous form using known techniques.
  • co-crystals of the present invention can be prepared by methods comprising:
  • the solvent used is selected from ethanol;
  • the solvent used is selected from isopropanol;
  • the solvent used is selected from water;
  • the solvent used Solvent is selected from ethanol;
  • step (b) adding cabozantinib to dissolve or suspend in a solvent together with or after step (a);
  • reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;
  • the specific conditions of the process can be adjusted, and the appropriate ratios are in the following molar ranges: 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.3-1:20, 0.4-1:20, 1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20, 1:0.8-1:20, 1:0.9-1:20, 1:1- 1:20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18, 1:7-1: 15. 1:8-1:13, 1:9-1:12 or 1:10-1:11.
  • a suitable ratio is about 1:1 (molar).
  • the period of time for pulping or stirring the mixture may be in the range of: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours, or 0.5-1 hours Hour. In some embodiments, the time period for pulping or stirring the mixture may be about 0.5 hours.
  • co-crystal compounds can be obtained by drying, filtering, centrifuging, pipetting, or combinations thereof. In some embodiments, co-crystal compounds can be obtained by centrifugation.
  • Cabozantinib co-crystal inhibits prostate cancer xenografts in nude mice
  • PC-3m cells in logarithmic growth phase were treated with 0.25% trypsin digestion solution, washed twice with PBS solution, and the cell suspension density of serum-free medium was adjusted to 1 ⁇ 10 7 /ml.
  • On an ultra-clean workbench use a 1ml disposable sterile syringe to inoculate 0.2ml of cell solution per nude mouse subcutaneously in the right quarter, with a cell number of 2 ⁇ 10 6 .
  • Subcutaneous nodules were visible to the naked eye 7 days after inoculation. 14 days after inoculation, the transplanted tumor can be seen to be about 5 mm 2 , which means that the modeling is successful.
  • the rats were randomly divided into 3 groups, 20 in each group. 1 20 rats in the treatment group were given 30 mg/kg (calculated as cabozantinib) cabozantinib and cabozantinib co-crystal for 14 consecutive days. 2 The 20 rats in the model group were administered with normal saline (30 mg/kg) for 14 consecutive days after successful modeling. 3The 20 rats in the control group were not modeled, but were only administered with normal saline (30 mg/kg) for 14 consecutive days. At the end of the treatment, the animals were sacrificed, the tumor tissues were dissected, and the tumor tissues of the three groups of rats were weighed and the tumor inhibition rates were calculated.
  • the tumor weight and tumor volume in the model group and the treatment group increased significantly; compared with the model group, the tumor weight decreased and the tumor inhibition rate increased significantly in the treatment group. And in the treatment group, the tumor inhibition rate of cabozantinib co-crystal was significantly higher than that of cabozantinib group and L-malate cabozantinib group.

Abstract

La présente invention concerne un co-cristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique, plus particulièrement une utilisation pour le traitement du carcinome médullaire de la thyroïde progressif (MTC), le cancer du rein et le cancer de la prostate. Le co-cristal a une bonne solubilité, une meilleure stabilité et une aptitude au développement du processus, etc, et le procédé de préparation est simple et peu coûteux, et présente des valeurs importantes pour l'optimisation et le développement du médicament dans le futur.
PCT/CN2022/136101 2021-12-03 2022-12-02 Cocristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique WO2023098853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111470192 2021-12-03
CN202111470192.9 2021-12-03

Publications (1)

Publication Number Publication Date
WO2023098853A1 true WO2023098853A1 (fr) 2023-06-08

Family

ID=86611551

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/136101 WO2023098853A1 (fr) 2021-12-03 2022-12-02 Cocristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique

Country Status (1)

Country Link
WO (1) WO2023098853A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (fr) * 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
CN102388024A (zh) * 2009-01-16 2012-03-21 埃克塞里艾克西斯公司 N-(4-{[6,7-双(甲基氧基)喹啉-4-基]氧基}苯基)-n’-(4-氟苯基)环丙烷-1,1-二甲酰胺的苹果酸盐及其用于癌症治疗的结晶型
CN104109124A (zh) * 2013-04-19 2014-10-22 正大天晴药业集团股份有限公司 卡博替尼·0.5苹果酸盐的晶体
US20180111903A1 (en) * 2015-03-25 2018-04-26 Sandoz Ag Crystalline Forms of Cabozantinib Phosphate And Cabozantinib Hydrochloride
CN108341773A (zh) * 2017-01-21 2018-07-31 南京华威医药科技开发有限公司 卡博替尼苹果酸盐的晶型ii
US20210332014A1 (en) * 2018-09-20 2021-10-28 Crystal Pharmaceutical (Suzhou) Co., Ltd. Cabozantinib malate crystal form, preparation method and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (fr) * 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
CN102388024A (zh) * 2009-01-16 2012-03-21 埃克塞里艾克西斯公司 N-(4-{[6,7-双(甲基氧基)喹啉-4-基]氧基}苯基)-n’-(4-氟苯基)环丙烷-1,1-二甲酰胺的苹果酸盐及其用于癌症治疗的结晶型
CN104109124A (zh) * 2013-04-19 2014-10-22 正大天晴药业集团股份有限公司 卡博替尼·0.5苹果酸盐的晶体
US20180111903A1 (en) * 2015-03-25 2018-04-26 Sandoz Ag Crystalline Forms of Cabozantinib Phosphate And Cabozantinib Hydrochloride
CN108341773A (zh) * 2017-01-21 2018-07-31 南京华威医药科技开发有限公司 卡博替尼苹果酸盐的晶型ii
US20210332014A1 (en) * 2018-09-20 2021-10-28 Crystal Pharmaceutical (Suzhou) Co., Ltd. Cabozantinib malate crystal form, preparation method and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YICHENG WANG，FENG CHENGLIANG, YANG SUQIN, JI MIN: "Recent Research Advances of Pharmaceutical Cocrystals", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 37, no. 3, 31 March 2013 (2013-03-31), pages 120 - 130, XP093068827 *

Similar Documents

Publication Publication Date Title
JP5511942B2 (ja) 組成物及びその使用
CN101248036B (zh) 邻乙酰基水杨酸与碱性氨基酸的盐和甘氨酸的稳定的活性物质络合物
CN106916177B (zh) 一种氘代的二肽硼酸或其酯类化合物及其合成方法与用途
JP2011517683A (ja) 疎水性タキサン誘導体の組成物およびその使用
CN102070618B (zh) 一种化合物及其晶体
TW201831191A (zh) 一種新的硼酸衍生物及其藥物組合物
WO2016155670A1 (fr) Inhibiteur de cdk, cristal eutectique d'inhibiteur de mek, et leur procédé de préparation
WO2021227146A1 (fr) Composé d'octanoate de n-[8-(2-hydroxybenzoyl)amino]monopotassium cristalin, son procédé de préparation et son utilisation
JP2019531314A (ja) 右旋性オキシラセタムの新しい結晶型、調製方法、用途
CN106474129A (zh) 一种帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法
WO2017041680A1 (fr) Composition pharmaceutique à base de vortioxétine ou d'un sel de celle-ci, et son procédé de préparation
CN101289438B (zh) 3-(3'-羟基)-丁基苯酞酯及其制法和用途
JPH05148274A (ja) ガリウム化合物
WO2023098853A1 (fr) Cocristal de cabozantinib, son procédé de préparation et son utilisation en tant que médicament ou dans une préparation pharmaceutique
WO2019080693A1 (fr) Composition pharmaceutique stable contenant un dérivé de médicament anti-inflammatoire non stéroïdien
US9364475B2 (en) Tablet formulation of a phosphatidylinositol 3-kinase inhibitor
WO2023098848A1 (fr) Co-cristal d'osimertinib, procédé de préparation et application en tant que médicament ou dans une formulation pharmaceutique
WO2020258660A1 (fr) Forme cristalline d'un hydrate d'hydrochlorure de valnemulin, son procédé de préparation et composition pharmaceutique contenant la forme cristalline
CN105732642B (zh) 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
CN111116462A (zh) 一种瑞戈非尼和汉黄芩素共晶体及其应用
JP2021527119A (ja) 塩形態
CN105753869B (zh) 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
CN108586485A (zh) 1-(4-羟亚胺基噻吩并[2,3-b]噻喃甲酰基)哌嗪类化合物及其应用
CN114573581B (zh) 5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制备与应用
CN114957137B (zh) N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物及其制备与应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22900657

Country of ref document: EP

Kind code of ref document: A1