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WO2018014834A1 - Composé de type phtalide substitué par 3-hydrocarbyl-5,6-dioxy et procédé pour sa préparation et utilisation correspondante - Google Patents

Composé de type phtalide substitué par 3-hydrocarbyl-5,6-dioxy et procédé pour sa préparation et utilisation correspondante Download PDF

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Publication number
WO2018014834A1
WO2018014834A1 PCT/CN2017/093408 CN2017093408W WO2018014834A1 WO 2018014834 A1 WO2018014834 A1 WO 2018014834A1 CN 2017093408 W CN2017093408 W CN 2017093408W WO 2018014834 A1 WO2018014834 A1 WO 2018014834A1
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methyl
compound according
benzoquinone
pharmaceutically acceptable
prodrug
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Ceased
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English (en)
Chinese (zh)
Inventor
杜俊蓉
陈雏
毛晓娜
吴燕
杨小佳
李彬
史梦琪
旷喜
李欣
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SI CHUAN UNIV
Sichuan Academy of Chinese Medicine Sciences SACMS
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SI CHUAN UNIV
Sichuan Academy of Chinese Medicine Sciences SACMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a kind of 3-hydrocarbyl-5,6-dioxy-substituted benzoquinone compound, a preparation method thereof and use thereof, and belongs to the technical field of medicine.
  • Neuroinflammation is closely related to the pathological process of many neurological diseases. These diseases involve Alzheimer's disease, vascular dementia, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, and brain tissue caused by ischemic stroke, hemorrhagic stroke, and trauma. Damage, etc. In addition, long-term or excessive inflammatory reactions may also lead to mental illness such as depression and anxiety. Inflammation in the brain is induced by activated microglia and reactive astrocytes. These cells are intrinsic immune cells in the brain. Under physiological conditions, they act to remove foreign substances such as pathogenic microorganisms and autologous necrotic cells in the central nervous system to maintain the stability of the inner environment of the nervous tissues.
  • glial cells Under pathological conditions, glial cells are Sustained by various pathogenic substances, a large number of inflammatory factors such as tumor necrosis factor- ⁇ , interleukin-1 ⁇ and interferon- ⁇ are secreted to form a pathological cascade, resulting in neuronal damage or even death, induced or Aggravate neurological lesions.
  • DAMPs risk-related molecular patterns of the release of neuronal cells after stroke - the peroxide reductase family (Prxs) loses antioxidant activity, but activates macrophage TLR2/TLR4 and mediates neuroinflammation.
  • the core pathophysiological mechanism of brain tissue damage after stroke [Nature Medicine. 2011, 17: 796; Nature Medicine. 2012, 18: 858].
  • Another important factor affecting the function of the nervous system is the lack of supply or imbalance of the body's material and energy, especially the lack of supply of glucose and oxygen and the imbalance of energy metabolism of other substances caused by cerebrovascular disease.
  • neurodegenerative diseases and abnormal glucose and lipid metabolism such as diabetes, obesity, and hypercholesterolemia.
  • the brain's utilization of sugar and cerebral blood flow decreased significantly, which led to changes in the blood flow of the patient's brain microcirculation, which limited the compensation of cerebral blood flow, and caused insufficient oxygen and glucose to the brain.
  • the disorder of energy metabolism in the nervous system causes neurological diseases.
  • Butylphthalide is a benzoquinone compound extracted from celery seeds. Chuanxiong, Angelica, Sakamoto, etc. also contain this ingredient. Butylphthalide of natural origin is an optically active left-handed body. Current person The synthetic racemate is used as a new chemical entity in China for the treatment of mild to moderate acute ischemic stroke.
  • butylphthalide has significant neuroprotective effects, can increase cerebral blood flow in the ischemic region and reconstruct microcirculation in the ischemic region, protect mitochondrial function, inhibit platelet aggregation and thrombosis, and improve energy after global cerebral ischemia.
  • the degree of metabolism and reduction of neurological damage involves multiple aspects of cerebral ischemic pathology and has significant therapeutic effects on stroke.
  • butylphthalide has certain effects on many neurological diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, diabetic neuropathy, memory disorder, stroke, traumatic brain injury, epilepsy, and depression. Improvement.
  • butyl benzoquinone also has some shortcomings.
  • the compound is a high-boiling oil, and its purification and purification have high requirements on production equipment; it is unstable in the body, and the metabolism is quickly cleared; it is an oil at room temperature, and it is not convenient to prepare an oral solid preparation, and currently only soft capsules are used for oral use. Has a special smell and may cause discomfort.
  • 2-( ⁇ -hydroxypentyl)benzoic acid and its salts rapidly undergo ring-closing reactions in plasma to form butylphthalide.
  • the reaction of butylphthalide with a base to convert to a prodrug, 2-( ⁇ -hydroxypentyl)benzoic acid and a salt thereof can improve the defect of poorly water-soluble butylphthalide.
  • 2-( ⁇ -hydroxypentyl)benzoic acid and its salts including inorganic salts such as potassium, sodium, calcium, magnesium, and zinc, and organic amine salts such as benzylamine, morpholine, and diethylamine, often have poor crystallinity.
  • an aqueous solution of a potassium salt or a sodium salt of 2-( ⁇ -hydroxypentyl)benzoic acid is alkaline (usually pH>9), and has a certain physiological irritancy.
  • the present inventors designed and synthesized a series of benzoquinone compounds against the deficiencies of the prior art, and selected benzoquinone compounds which are more active, safer and have better drug-forming properties.
  • the Applicant has proposed the present invention in order to overcome the drawbacks and deficiencies of butyl benzoquinone and to obtain better benzoquinones.
  • a benzoquinone compound or a pharmaceutically acceptable solvate, prodrug thereof, which is selected from the group consisting of Formula I:
  • R 1 is selected from a C 3 -C 6 hydrocarbon group; and R 2 and R 3 are independently selected from hydrogen, C 1 -C 3 alkyl, acetyl.
  • hydrocarbyl group as used in the present invention means a linear or branched aliphatic hydrocarbon group including an alkyl group, an alkenyl group, and an alkynyl group.
  • the "solvate” as used in the present invention means an aggregate in which a compound represented by the formula I is associated with one or more solvent molecules during crystallization.
  • the solvent molecule can be water or other organic solvent (e.g., ethanol, isopropanol, diethyl ether, ethyl acetate, acetone, etc.).
  • the "prodrug” as used in the present invention means a carboxylic acid and a salt thereof which are produced by reacting a phenylhydrazine compound represented by the formula I with a base and undergoing a ring opening reaction of the lactone.
  • the above base includes inorganic bases (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc.), organic bases (such as benzylamine, morpholine, ethylenediamine, ethanolamine, piperazine, choline, methylamine). , dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, etc.).
  • the above carboxylic acid and its salt can be converted into a parent drug (benzoquinone compound represented by the formula I) under physiological conditions in vivo.
  • the benzoquinone compound of the invention is characterized in that R 1 is selected from the group consisting of n-propyl, n-butyl, n-pentyl, 2-allyl, 2-enbutyl, 3 -enylbutyl, 1-methyl-3-enylbutyl, 1-methyl-2-allyl, 2-methyl-2-allyl, 1,1-dimethyl-2-ene 1,1,2-dimethyl-2-allyl, 3-methyl-2-enylbutyl, 2,2-dimethyl-3-enylbutyl, 3-methyl-3-ene Base, 4-methyl-3-enpentyl, 1-methyl-1-vinyl, 1-ethyl-1-vinyl, 1-propyl-1-vinyl, 2-propargyl, 3 - alkynyl butyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, methyl, acetyl.
  • the benzoquinone compound of the present invention is further preferably selected from the following compounds:
  • the benzoquinone compound can be prepared by the following method:
  • Compound 1 was reacted with HCl and a 37% formaldehyde solution at 10 to 80 ° C for 4 to 12 hours to obtain Compound 2.
  • the compound 2 is reacted with N-bromosuccinimide (NBS) at 20 to 100 ° C for 2 to 8 hours using CCl 4 or benzene as a solvent and benzoyl peroxide as a catalyst to obtain a compound 3.
  • NBS N-bromosuccinimide
  • Compound 3 is reacted with water at 20 to 100 ° C for 1 to 4 hours to form Compound 4.
  • Compound 4 is reacted with a halogenated alkaloid Grignard reagent (e.g., R 1 MgBr, R 1 MgCl, etc.) to give the target compound 5.
  • a halogenated alkaloid Grignard reagent e.g., R 1 MgBr, R 1 MgCl, etc.
  • a pharmaceutical composition comprising a safe and effective amount of one or more benzoquinone compounds, and pharmaceutically acceptable solvates, prodrugs thereof.
  • composition as used in the present invention means a product obtained by mixing one or more substances or components.
  • the composition of the present invention comprises 1% by weight to 95% by weight, preferably 10% by weight to 80% by weight, of the benzoquinone compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug thereof, The total weight of the pharmaceutical composition.
  • the "safe and effective amount" as used in the present invention means that the benzoquinone compound of the present invention is administered in a dose sufficient to significantly improve the condition without causing serious side effects.
  • a safe and effective amount of a compound of the invention may depend on the route of administration, The patient's age, weight, type of disease, and severity thereof vary. For a person weighing 60 kg, the daily dose is usually from 10 mg to 1500 mg, preferably from 30 mg to 600 mg. It can be administered once or in multiple doses.
  • the pharmaceutical composition may be further added with one or more pharmaceutically acceptable carriers to prepare a pharmaceutically acceptable pharmaceutical preparation.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. .
  • compatibil it is meant herein that the components of the composition are capable of blending with the benzoquinone compounds of the invention and with each other without significantly reducing the efficacy of the benzoquinone compound.
  • Pharmaceutically acceptable carriers include sugars (such as sucrose, lactose, glucose, etc.), starches (such as potato starch, corn starch, etc.), cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, Cellulose acetate, etc., dextrin and its derivatives, micronized silica gel, gelatin, talc, calcium sulfate, solid lubricants (such as magnesium stearate, stearic acid, etc.), vegetable oils (such as soybean oil, sesame oil, Peanut oil, olive oil, castor oil, cottonseed oil, corn germ oil, palm oil, etc.), alcohol solvents (such as ethanol, propylene glycol, glycerin, mannitol, sorbitol, polyethylene glycol, etc.), surfactants, emulsifiers , wetting agents, colorants, flavors, stabilizers, antioxidants, preservatives, no heat source water.
  • sugars such as sucrose, lacto
  • the "pharmaceutical preparation" includes tablets, capsules, pills, granules, pills, powders, troches, injections, freeze-dried powders, syrups, oral liquids, patches, inhalation powders, Sprays are administered orally, intravenously, intramuscularly, subcutaneously, sublingually, transdermally, orally sprayed, or nasally.
  • a fourth aspect of the invention provides the use of the phenylhydrazine compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug thereof, or a pharmaceutical composition according to the third aspect, for use in the preparation of prophylaxis and/or A drug that treats nervous system diseases.
  • neurode diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, ischemic stroke, hemorrhagic stroke, and brain trauma.
  • nerve damage depression, vascular dementia, neuropathic pain.
  • the prevention and/or treatment of a nervous system disease is achieved by inhibiting excessive release of inflammatory factors under pathological conditions.
  • the prevention and/or treatment of a nervous system disorder is achieved by improving brain blood vessels and blood flow states, and regulating energy metabolism in the brain.
  • a fifth aspect of the invention provides the use of the phenylhydrazine compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug or a pharmaceutical composition according to the third aspect, for:
  • the benzoquinone compound disclosed in the invention can alleviate peroxidase 4 (Prx4)-induced cell inflammatory damage, has significant neuroprotective effect, and has better effect than butylphthalide;
  • the benzoquinone compound disclosed in the present invention is crystalline Sexual solid, not easy to absorb moisture, no obvious odor, stable physicochemical properties, can be more conveniently prepared than the butyl benzoquinone which is oily at normal temperature;
  • the benzoquinone compound disclosed in the present invention is at pH 1 ⁇ It is stable in the range of 9 and is superior to butylphthalide in plasma.
  • the benzoquinone compound disclosed in the present invention has low toxicity and good safety.
  • Figure 1 shows the concentration of NO in the blank group, model group, and RAW264.7 macrophages treated with different concentrations of the compounds of the present invention (C-1 to C-6) and butylphthalide (NBP). Compared with the model group: *P ⁇ 0.05, **P ⁇ 0.01.
  • Figure 2 is a graph showing the effects of the compounds (C-1 to C-3) and butylphthalide (NBP) of the present invention on neuropathological changes of cerebral ischemia in mice.
  • RAW264.7 macrophages in the logarithmic growth phase were adjusted to a cell density of 5 ⁇ 10 5 /ml, seeded in a 96-well plate, 100 ⁇ l / well, and cultured in a 37 ° C, 5% CO 2 incubator. After the cells were attached for 20 hours, the medium in the well was discarded, and 80 ⁇ l/well of basal medium was added, and 10 ⁇ l/well of the test compound at different concentrations was added, and after 1 hour, Prx4 was added to a final concentration of 20 nmol/ml. The cell supernatant was collected after 20 hours. The color content was measured by NaNO 2 using a colorimetric method, and the NO content was detected at a wavelength of 550 nm. The results are shown in Fig. 1.
  • mice Compared with the sham operation group (Sham group), the bilateral common carotid arteries in the mice were temporarily ligated to cause cerebral ischemia, causing neurobehavioral disorders, neuronal loss and astrocyte overactivation in the model group (Model group); After cerebral ischemia and reperfusion, different phenylhydrazine compounds were given.
  • C-1, C-2 and C-3 all showed strong neuroprotective effects, which could not only improve the mice 24 hours after 48 hours of hypoperfusion.
  • Hour and 72 hours of neurobehavioral function also It can increase the number of neurons in the hippocampus and striatum brain regions, and the effect is better than NBP.
  • SPF grade ICR mice 18-20 g, male and female, 3 days after adaptive feeding, fasted for 12 hours and weighed randomly into groups: vehicle group and drug group (C-1, C-2, C-3).
  • vehicle group and drug group C-1, C-2, C-3.
  • Each test compound was prepared by suspending 0.5% carboxymethylcellulose sodium solution before use, and the dosage was 1.0 g/20 ml/kg; the vehicle group was intragastrically administered with 20 ml/kg of blank solvent. After the administration, the animals were kept in a single cage within 48 hours, and the animals were continuously observed 2 hours after the drug, and the animals were weighed 7 days and 14 days after the drug.
  • C-1, C-2, C-3 gavage dose of 1.0g/kg showed no adverse reactions in ICR mice; during the 14-day observation period, each drug-administered group and the vehicle group were small. There was no difference in body weight gain and no animal death. The results showed that the safe doses of C-1, C-2 and C-3 administered to mice were more than 1.0g/kg.

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Abstract

L'invention porte sur un composé de type phtalide substitué par 3-hydrocarbyl-5,6-dioxy, sur un procédé pour sa préparation et une utilisation correspondante. La structure du composé de type phtalide est telle que représentée dans la formule (I) : dans laquelle les définitions de R1, R2 et R3 sont telles que décrites dans la description et les revendications. Le composé de type phtalide est facile à synthétiser, présente une bonne stabilité et une bonne sécurité et est doté d'une activité anti-inflammatoire et d'effets neuroprotecteurs considérables et peut être utilisé dans la préparation de médicaments destinés à prévenir et/ou à traiter des maladies du système nerveux.
PCT/CN2017/093408 2016-07-19 2017-07-18 Composé de type phtalide substitué par 3-hydrocarbyl-5,6-dioxy et procédé pour sa préparation et utilisation correspondante Ceased WO2018014834A1 (fr)

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CN201610566577.8 2016-07-19
CN201610566577.8A CN106432161A (zh) 2016-07-19 2016-07-19 一类3‑烃基‑5,6‑二氧取代苯酞化合物及其制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112794831A (zh) * 2021-04-06 2021-05-14 北京理工大学 3-(3′-羟基丁基)异苯并呋喃-1(3h)-酮衍生物及其组合物、制备方法和用途
KR20220156597A (ko) * 2020-03-20 2022-11-25 씨에스피씨 엔비피 파머슈티컬 캄파니 리미티드 부틸프탈라이드 및 이의 유도체의 용도
WO2023001164A1 (fr) * 2021-07-21 2023-01-26 江苏正大丰海制药有限公司 Composé pour le traitement d'une maladie associée à une lésion cérébrale ischémique

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432161A (zh) * 2016-07-19 2017-02-22 四川大学 一类3‑烃基‑5,6‑二氧取代苯酞化合物及其制备方法和用途
CN108727352B (zh) * 2017-04-14 2021-04-23 四川大学 一类哌啶烷氨甲酰基苯酞类化合物、其制备方法和用途
CN109111415B (zh) * 2018-10-25 2022-08-23 安徽中医药大学 一类石斛生物碱衍生物、制备方法和医药用途
CN114478450A (zh) * 2022-01-10 2022-05-13 四川大学 苄氧基苯酞类化合物、其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101184484A (zh) * 2005-05-24 2008-05-21 帝斯曼知识产权资产管理有限公司 用于治疗炎性失调的藁本内酯衍生物
CN101402623A (zh) * 2008-11-19 2009-04-08 中国科学院上海有机化学研究所 具有生物活性的3-取代苯酞类化合物
CN101563080A (zh) * 2006-08-11 2009-10-21 帝斯曼知识产权资产管理有限公司 用于治疗中枢神经病症的藁本内酯衍生物
WO2013102935A2 (fr) * 2012-01-03 2013-07-11 Council Of Scientific & Industrial Research Annélation médiée par le cuivre pour la synthèse efficace de phtalides substitués en position 3
CN106432161A (zh) * 2016-07-19 2017-02-22 四川大学 一类3‑烃基‑5,6‑二氧取代苯酞化合物及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101184484A (zh) * 2005-05-24 2008-05-21 帝斯曼知识产权资产管理有限公司 用于治疗炎性失调的藁本内酯衍生物
CN101563080A (zh) * 2006-08-11 2009-10-21 帝斯曼知识产权资产管理有限公司 用于治疗中枢神经病症的藁本内酯衍生物
CN101402623A (zh) * 2008-11-19 2009-04-08 中国科学院上海有机化学研究所 具有生物活性的3-取代苯酞类化合物
WO2013102935A2 (fr) * 2012-01-03 2013-07-11 Council Of Scientific & Industrial Research Annélation médiée par le cuivre pour la synthèse efficace de phtalides substitués en position 3
CN106432161A (zh) * 2016-07-19 2017-02-22 四川大学 一类3‑烃基‑5,6‑二氧取代苯酞化合物及其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARFIELD, M. ET AL.: "Interproton Spin-Spin Coupling across a Dual Path in 2, 5-Dihydrofurans and Phthalans", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 97, no. 18, 3 September 1975 (1975-09-03), pages 5160 - 5167, XP055455099 *
MAHENDAR, L. ET AL.: "Domino [Pd]-Catalysis: One-Pot Synthesis of Isobenzofuran-1 (3H)-ones", J. ORG. CHEM., vol. 81, no. 17, 18 August 2016 (2016-08-18), pages 7685 - 7691, XP055455091 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220156597A (ko) * 2020-03-20 2022-11-25 씨에스피씨 엔비피 파머슈티컬 캄파니 리미티드 부틸프탈라이드 및 이의 유도체의 용도
EP4122462A4 (fr) * 2020-03-20 2024-03-20 Cspc Nbp Pharmaceutical Co., Ltd. Utilisation de butylphtalide et dérivé associé
KR102847818B1 (ko) 2020-03-20 2025-08-19 씨에스피씨 엔비피 파머슈티컬 캄파니 리미티드 부틸프탈라이드 및 이의 유도체의 용도
CN112794831A (zh) * 2021-04-06 2021-05-14 北京理工大学 3-(3′-羟基丁基)异苯并呋喃-1(3h)-酮衍生物及其组合物、制备方法和用途
WO2023001164A1 (fr) * 2021-07-21 2023-01-26 江苏正大丰海制药有限公司 Composé pour le traitement d'une maladie associée à une lésion cérébrale ischémique

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