WO2023109859A1 - Composé de stilbène et son utilisation dans la prévention et/ou le traitement de maladies liées au système nerveux central - Google Patents

Composé de stilbène et son utilisation dans la prévention et/ou le traitement de maladies liées au système nerveux central Download PDF

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Publication number
WO2023109859A1
WO2023109859A1 PCT/CN2022/138972 CN2022138972W WO2023109859A1 WO 2023109859 A1 WO2023109859 A1 WO 2023109859A1 CN 2022138972 W CN2022138972 W CN 2022138972W WO 2023109859 A1 WO2023109859 A1 WO 2023109859A1
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Prior art keywords
nervous system
central nervous
disease
inhibit
formula
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PCT/CN2022/138972
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English (en)
Chinese (zh)
Inventor
陈明
马志龙
贾剑敏
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上海泽德曼医药科技有限公司
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Priority claimed from CN202111555173.6A external-priority patent/CN116265421B/zh
Application filed by 上海泽德曼医药科技有限公司 filed Critical 上海泽德曼医药科技有限公司
Publication of WO2023109859A1 publication Critical patent/WO2023109859A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring

Definitions

  • the present invention claims the patent application number 202111537597.X submitted to the State Intellectual Property Office of China on December 15, 2021, entitled “Compounds for the Prevention or Treatment of Central Nervous System-related Diseases” and filed on December 17, 2021.
  • the patent application No. 202111555173.6, filed with the State Intellectual Property Office of China on the 1st, is the priority of the earlier application titled “Compounds for the Prevention or Treatment of Central Nervous System Related Diseases".
  • the entirety of the prior application is incorporated by reference into the present application.
  • the present disclosure relates to stilbene compounds, especially the use of such compounds in the prevention and/or treatment of diseases related to the central nervous system, and belongs to the field of medicine.
  • the central nervous system (Central Nervous System, CNS) is the main part of the nervous system, which includes the spinal cord located in the spinal canal and the brain located in the cranial cavity. Or the brain and spinal cord and the connections between them. In the central nervous system, a large number of nerve cells come together to organically form a network or circuit. The main functions of the central nervous system are to transmit, store and process information, generate various mental activities, and dominate and control the behavior of animals.
  • CNS Central Nervous System
  • Central nervous system diseases can be roughly divided into two categories.
  • the first category is brain diseases caused by brain damage, such as Parkinson's disease, Alzheimer's disease and brain tumors, etc.; the second category is motor and sensory dysfunction caused by spinal cord injuries. wait.
  • Microglia as macrophages in the brain, are one of the key players in central nervous system immunity. They are distributed throughout the parenchyma, accounting for about 10% to 20% of the total number of glial cells in the brain. Experimental and epidemiological evidence has shown that the activation of microglia is associated with neurodegenerative diseases, such as stroke, Alzheimer's disease, cognitive dysfunction, etc.
  • the blood-brain barrier maintains a relatively stable environment in the nervous system by restricting compounds from entering the central nervous system, and protects nerve cells from harmful substances.
  • the blood-brain barrier also restricts the pathways needed for compounds carried by the blood and nutrients necessary for normal metabolism to reach the central nervous system.
  • the existence of this limitation makes it difficult for many drugs to enter the central nervous system, which has become a key bottleneck in the current drug treatment of central nervous system diseases. Therefore, the development of drugs that can effectively penetrate the blood-brain barrier and treat diseases related to the central nervous system is of great significance for the prevention and treatment of such diseases.
  • the drug is used for at least one of the following purposes:
  • the compound represented by the formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1), that is, 5-[( E)-2-Styryl]-2-isopropyl-1,3-benzenediol:
  • the present disclosure also provides the use of the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, which is used for at least one of the following uses:
  • the present disclosure also provides a method for preventing and/or treating central nervous system-related diseases or disorders, comprising administering a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to patients in need of patients.
  • the present disclosure also provides a method for inhibiting cytokine activity, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.
  • the present disclosure also provides a method for inhibiting glial cell activation, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.
  • the present disclosure also provides a method for inhibiting glutamic acid concentration in vivo, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.
  • the present disclosure also provides a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, which is used for at least one of the following purposes:
  • the present disclosure also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the drug
  • the composition is used for at least one of the following purposes:
  • the present disclosure also provides the use of the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used to inhibit the concentration of glutamic acid in the body.
  • the cytokines may include, but are not limited to, at least one selected from the following: TNF- ⁇ , IL-1 ⁇ , IL-6, and IL-10.
  • the glial cells may be glial cells present in the central nervous system, including but not limited to at least one selected from the following: astrocytes, oligodendrocytes cells and microglia.
  • the drug or pharmaceutical composition may be selected from cytokine inhibitors, such as TNF- ⁇ inhibitors and interleukin inhibitors; wherein, the interleukins may be selected from, for example, IL-1 ⁇ , IL-6 or IL-10.
  • the drug or pharmaceutical composition may be selected from activation inhibitors of glial cells.
  • the drug or pharmaceutical composition may be selected from inhibitors of glutamate concentration in vivo.
  • the drug or pharmaceutical composition may be selected from therapeutic or preventive agents for central nervous system-related diseases or disorders.
  • the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and its medicine or pharmaceutical composition can treat the disease or disease by passing through the blood-brain barrier. Prophylactic or therapeutic effects, as well as inhibition of cytokine secretion, glial cell activation and glutamate concentration.
  • the pharmaceutically acceptable salt may be selected from addition salts of compounds of formula (I) or formula (I-1) with bases.
  • the central nervous system-related disease or disorder may be a disease or disorder associated with secretion of cytokines and/or activation of glial cells.
  • the central nervous system-related disease or disease may be a disease or disease related to central nervous system inflammation, which includes but is not limited to one selected from the following: neuroinflammation, neurodegenerative Disease, stroke, epilepsy, traumatic brain injury, shock, HIV dementia, glaucoma, multiple sclerosis.
  • said neurodegenerative disease is selected from Alzheimer's disease, cognitive impairment, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy, Parkinson's disease, Huntington's Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, ataxia telangiectasia, amyotrophic lateral sclerosis.
  • the central nervous system includes the brain and spinal cord.
  • secretion such as “secretion of a cytokine”
  • release such as “release of a cytokine”
  • the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof can efficiently penetrate the blood-brain barrier, inhibit the inflammatory response of the central nervous system, and can be used to prevent and/or Treat diseases or conditions related to the central nervous system, inhibit the secretion of cytokines, inhibit the activation of glial cells, and inhibit the concentration of glutamate in the body.
  • Fig. 1 is a broken line graph of changes in brain tissue drug concentration after intraperitoneal injection of the test compound in rats in Example 1.
  • FIG. 2 is a line graph of the inhibitory rate of the test compound on TNF- ⁇ in Example 2.
  • Fig. 3 is a line graph of the inhibition rate of glutamate by the test compound in Example 3.
  • Fig. 4 is a histogram of the inhibitory rate of the test compound in Example 4 to rat glial cell cytokines.
  • rats were randomly divided into three groups A, B and C, and 10 mg/kg of the test compound was injected intraperitoneally respectively, and the rats in groups A, B and C were killed by decapitation at 15 min, 1.5 h and 6 h after administration, respectively.
  • Rat primary microglial cells (3.5 ⁇ 10 4 cells/well) were cultured in DMEM medium containing 2% fetal bovine serum in a 96-well plate, and a drug group and a control group were respectively set up. Take out the medium from the well, add the drug-containing medium containing different concentrations of the test compound (0.01 ⁇ M, 0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M) in the drug group, add blank medium in the control group, and continue to cultivate for 30 minutes.
  • Rat primary microglial cells (3.5 ⁇ 10 4 cells/well) were cultured in 96-well plates with phenol red-free and serum-free DMEM medium containing 2 mM glutamine, and drug groups and control groups were set up, respectively. Take out the medium from the well, add the drug-containing medium containing different concentrations of the test compound (0.01 ⁇ M, 0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M) in the drug group, add blank medium in the control group, and continue to cultivate for 30 minutes.
  • LPS lipopolysaccharide
  • Rat primary microglial cells were cultured in DMEM medium containing 2% fetal bovine serum in 4 culture dishes, and drug groups 1 and 2 and control groups 1 and 2 were set up respectively. Take out the culture medium, add the culture medium containing 5 ⁇ M test compound in the medication group, add the blank culture medium in the control group, after continuing to cultivate for 48h, use R&D Systems DuoSet ELISA to measure the IL-1 ⁇ level in the medication group 1 and the control group 1 respectively, The levels of IL-6 in the medication group 2 and the control group 2 were measured, and the inhibitory rate of the test compound on IL-1 ⁇ and IL-6 was obtained. The results are shown in FIG. 4 .
  • the compound disclosed in the present disclosure has a high inhibitory rate on both IL-1 ⁇ and IL-6.

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

Abstract

L'invention concerne un composé tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Le composé peut pénétrer de manière efficace dans une barrière hémato-encéphalique, inhibe une réponse inflammatoire du système nerveux central, peut être utilisé pour prévenir et/ou traiter des maladies ou des états liés au système nerveux central, inhiber la sécrétion de cytokines, inhiber l'activation de cellules gliales et inhiber la concentration d'acide glutamique in vivo. L'invention concerne un médicament potentiel pour la prévention et/ou le traitement de maladies liées au système nerveux central.
PCT/CN2022/138972 2021-12-15 2022-12-14 Composé de stilbène et son utilisation dans la prévention et/ou le traitement de maladies liées au système nerveux central WO2023109859A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202111537597 2021-12-15
CN202111537597.X 2021-12-15
CN202111555173.6A CN116265421B (zh) 2021-12-17 2021-12-17 用于预防或治疗中枢神经系统相关疾病的化合物
CN202111555173.6 2021-12-17

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WO2023109859A1 true WO2023109859A1 (fr) 2023-06-22

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016092493A1 (fr) * 2014-12-12 2016-06-16 Glaxosmithkline Intellectual Property Development Limited Nouvelle méthode d'utilisation
CN108066279A (zh) * 2018-01-13 2018-05-25 天津双硕医药科技有限公司 一种含有苯烯莫德的外用乳膏组合物
CN112250546A (zh) * 2020-10-14 2021-01-22 中山大学 一种（e)-3，5-二羟基-4-异丙基二苯乙烯的合成方法
CN113473969A (zh) * 2019-01-27 2021-10-01 索尔-格尔科技有限公司 用局部塔匹那洛夫组合式组合物治疗皮肤病症
US20210346279A1 (en) * 2020-05-07 2021-11-11 Sol-Gel Technologies Ltd. Compositions comprising tapinarof for the treatment of pruritis

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016092493A1 (fr) * 2014-12-12 2016-06-16 Glaxosmithkline Intellectual Property Development Limited Nouvelle méthode d'utilisation
CN108066279A (zh) * 2018-01-13 2018-05-25 天津双硕医药科技有限公司 一种含有苯烯莫德的外用乳膏组合物
CN113473969A (zh) * 2019-01-27 2021-10-01 索尔-格尔科技有限公司 用局部塔匹那洛夫组合式组合物治疗皮肤病症
US20210346279A1 (en) * 2020-05-07 2021-11-11 Sol-Gel Technologies Ltd. Compositions comprising tapinarof for the treatment of pruritis
CN112250546A (zh) * 2020-10-14 2021-01-22 中山大学 一种（e)-3，5-二羟基-4-异丙基二苯乙烯的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HU, YUQING ET AL.: "Effects of Benvimod on the proliferation of HaCaT cells, the secretion of inflammatory factors and the production of skin barrier factors", CHINESE JOURNAL OF DERMATOLOGY, vol. 53, no. 12, 31 December 2020 (2020-12-31), XP009547222 *
SUSAN H. SMITH, JAYAWICKREME CHANNA, RICKARD DAVID J., NICODEME EDWIGE, BUI THI, SIMMONS CATHY, COQUERY CHRISTINE M., NEIL JESSICA: "Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans", JOURNAL OF INVESTIGATIVE DERMATOLOGY, ELSEVIER, NL, vol. 137, no. 10, 31 October 2017 (2017-10-31), NL , pages 2110 - 2119, XP055727670, ISSN: 0022-202X, DOI: 10.1016/j.jid.2017.05.004 *

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