WO2018059531A1 - Forme cristalline d'un médicament antagoniste du récepteur de l'adénosine a 2a , son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un médicament antagoniste du récepteur de l'adénosine a 2a , son procédé de préparation et son utilisation Download PDF

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Publication number
WO2018059531A1
WO2018059531A1 PCT/CN2017/104218 CN2017104218W WO2018059531A1 WO 2018059531 A1 WO2018059531 A1 WO 2018059531A1 CN 2017104218 W CN2017104218 W CN 2017104218W WO 2018059531 A1 WO2018059531 A1 WO 2018059531A1
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WIPO (PCT)
Prior art keywords
crystal form
preparation
tozadenant
present
drug
Prior art date
Application number
PCT/CN2017/104218
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
翟晓婷
鄢楷强
张晓宇
Original Assignee
苏州晶云药物科技有限公司
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Publication date
Application filed by 苏州晶云药物科技有限公司 filed Critical 苏州晶云药物科技有限公司
Publication of WO2018059531A1 publication Critical patent/WO2018059531A1/fr

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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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Parkinson's disease usually occurs in elderly people over the age of 60, and about 1% of the elderly suffer from the disease; men are more likely to get Parkinson's disease than women. Parkinson's disease usually survives 7-14 years after diagnosis.
  • the stability of the drug is an important aspect in the quality evaluation of the drug. It is of great significance to reduce the drug dissolution rate and bio-profitability due to the change of the crystal form, which is effective for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the thermodynamically more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystals; it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent and controllable sample quality and ensuring the preparation of the product.
  • the dissolution profile does not change as the storage time changes.
  • the "volatilization” is accomplished by conventional methods in the art, such as fast swinging, slow swinging, and the like.
  • the fast swing means that the compound is dissolved in a specific system, and after being filtered, the open mouth is rapidly volatilized at a specific temperature.
  • the slow swing means that the compound is dissolved in a specific system, and after filtration, a sealing film is applied to the mouth of the container, and a small hole is marked on the needle by the needle to slowly evaporate.
  • Figure 3 is an XRPD overlay of the crystalline form CS1 obtained in Example 1 according to Example 1 of the present invention placed in a constant temperature and humidity chamber at 25 ° C / 60% RH, 40 ° C / 75% RH and placed in an oven at 80 ° C for a period of time (from Top to bottom is the X-ray pattern of Tozadenant crystal form CS1, placed at 25 ° C / 60% RH for one year, 40 ° C / 75% RH for one year and 80 ° C for one week.
  • Example 4 is a DVS diagram of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Fig. 5 is a PSD diagram of a crystal form CS1 in the fifth embodiment of the present invention.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Tozadenant used in the following examples was prepared according to the method described in WO2005116026 A1.
  • the prepared Tozadenant crystal form CS1 sample was prepared into a saturated solution with SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (artificial intestinal juice in fed state), pH 6.5 FaSSIF (artificial intestinal juice in fasting state), respectively, in 1 hour.
  • SGF simulated artificial gastric juice
  • pH 5.0 FeSSIF artificial intestinal juice in fed state
  • pH 6.5 FaSSIF artificial intestinal juice in fasting state
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 4 hours and 24 hours.
  • HPLC high performance liquid chromatography
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline d'un médicament antagoniste du récepteur de l'adénosine A 2A , un tozadenant, son procédé de préparation et son utilisation. Le tozadenant préparé a une forme cristalline CS1, peut être utilisé pour préparer une formulation de médicament antagoniste du récepteur de l'adénosine A 2A , fournit une nouvelle option pour la préparation d'une formulation de médicament contenant du tozadenant, et a une valeur cruciale pour le développement du médicament.
PCT/CN2017/104218 2016-09-30 2017-09-29 Forme cristalline d'un médicament antagoniste du récepteur de l'adénosine a 2a , son procédé de préparation et son utilisation WO2018059531A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610871979.9 2016-09-30
CN201610871979 2016-09-30

Publications (1)

Publication Number Publication Date
WO2018059531A1 true WO2018059531A1 (fr) 2018-04-05

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PCT/CN2017/104218 WO2018059531A1 (fr) 2016-09-30 2017-09-29 Forme cristalline d'un médicament antagoniste du récepteur de l'adénosine a 2a , son procédé de préparation et son utilisation

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WO (1) WO2018059531A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146795A1 (fr) 2019-01-11 2020-07-16 Omeros Corporation Procédés et compositions pour le traitement du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1956983A (zh) * 2004-05-24 2007-05-02 弗·哈夫曼-拉罗切有限公司 4－羟基－4－甲基－哌啶－1－甲酸(4－甲氧基－7－吗啉－4－基－苯并噻唑－2－基)－酰胺
CN101873799A (zh) * 2007-07-23 2010-10-27 辛诺西亚治疗公司 用于治疗创伤后应激障碍的4-羟基-4-甲基-哌啶-1-羧酸(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺
CN103429221A (zh) * 2010-11-05 2013-12-04 拜奥太治疗公司 作为认知和运动功能增强剂的a2a拮抗剂
CN104873531A (zh) * 2015-05-06 2015-09-02 浙江省亚热带作物研究所 一种腺苷受体激动试剂及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1956983A (zh) * 2004-05-24 2007-05-02 弗·哈夫曼-拉罗切有限公司 4－羟基－4－甲基－哌啶－1－甲酸(4－甲氧基－7－吗啉－4－基－苯并噻唑－2－基)－酰胺
CN101873799A (zh) * 2007-07-23 2010-10-27 辛诺西亚治疗公司 用于治疗创伤后应激障碍的4-羟基-4-甲基-哌啶-1-羧酸(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺
CN103429221A (zh) * 2010-11-05 2013-12-04 拜奥太治疗公司 作为认知和运动功能增强剂的a2a拮抗剂
CN104873531A (zh) * 2015-05-06 2015-09-02 浙江省亚热带作物研究所 一种腺苷受体激动试剂及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OLIVIER RASCOL ET AL., NEW TREATMENTS FOR LEVODOPA-INDUCED MOTOR COMPLICATIONS, vol. 30, no. 11, 21 August 2015 (2015-08-21), pages 1453 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146795A1 (fr) 2019-01-11 2020-07-16 Omeros Corporation Procédés et compositions pour le traitement du cancer

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