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WO2025131037A1 - Dérivé de benzothioate de trifluoroalkyle thioalkyle substitué, son procédé de préparation et son utilisation - Google Patents

Dérivé de benzothioate de trifluoroalkyle thioalkyle substitué, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025131037A1
WO2025131037A1 PCT/CN2024/140882 CN2024140882W WO2025131037A1 WO 2025131037 A1 WO2025131037 A1 WO 2025131037A1 CN 2024140882 W CN2024140882 W CN 2024140882W WO 2025131037 A1 WO2025131037 A1 WO 2025131037A1
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WO
WIPO (PCT)
Prior art keywords
benzoic acid
substituted benzoic
trifluoroalkylthioalkylthioester
compound
derivative
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/CN2024/140882
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English (en)
Chinese (zh)
Inventor
戚建华
陈丹妮
向兰
陈梦
李亚静
王颖
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Zhejiang University ZJU
Original Assignee
Zhejiang University ZJU
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Filing date
Publication date
Priority claimed from CN202410086203.0A external-priority patent/CN120192256A/zh
Priority claimed from CN202410087623.0A external-priority patent/CN120189404A/zh
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Publication of WO2025131037A1 publication Critical patent/WO2025131037A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61P25/28—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
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/26—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to substituted benzoic acid trifluoroalkylthioalkylthioester derivatives and preparation methods and applications thereof.
  • BV-2 microglia are a common cell model for studying inflammation. When brain damage such as ischemia occurs, microglia are the first to respond to the damage and transform into an active state. Activated microglia can differentiate into different phenotypes, including M1 that causes neurological damage and M2 phenotypes that have neuroprotective effects.
  • LPS Lipopolysaccharide
  • BV-2 microglia can induce BV-2 microglia to activate into M1 phenotype and promote the release of various pro-inflammatory mediators, thus causing inflammatory response.
  • BV-2 microglia have simple culture conditions, can be cultured continuously, are easy to operate and have low cost.
  • lead compounds with anti-inflammatory activity can be screened out by high-throughput.
  • the brains of mice fed a high-fat diet and normal aging mice are also affected by inflammation, which in turn causes various neurological diseases.
  • Patent document with publication number CN111777588A discloses a phenylpropanoid compound from Pseudostinex and its application.
  • the invention extracts a new type of phenylpropanoid compound from Pseudostinex.
  • the new type of phenylpropanoid compound exhibits an inhibitory effect on the inflammatory mediator NO produced by LPS-induced BV-2 cells, has a significant anti-inflammatory effect, and is non-toxic to cells.
  • the compound can be used to prepare drugs related to inflammation.
  • Patent document with publication number CN111574581A discloses low-toxicity, anti-inflammatory ursolic acid derivatives and their preparation methods and applications.
  • the invention uses ursolic acid as a lead compound for structural modification to obtain a low-toxicity, anti-inflammatory new ursolic acid derivative.
  • the derivative has significant inhibitory activity on lipopolysaccharide-induced NO release in RAW264.7 cells and has extremely low cytotoxicity.
  • the first object of the present invention is to provide a substituted benzoic acid trifluoroalkylthioalkylthioester derivative, which has a very significant anti-inflammatory and neuroprotective effect on BV-2 microglia, and the anti-inflammatory activity is equivalent to that of the positive drug butylphthalide, and the active concentration is much lower than that of the positive drug, and can be used for the preparation and application of anti-inflammatory and neuroprotective drugs.
  • a substituted benzoic acid trifluoroalkylthioalkylthioester derivative whose structure is shown in formula (I):
  • R 1 and R 2 are OH, OAc or H
  • X and Y are linear or branched alkyl groups having 1 to 9 carbon atoms.
  • the present invention also provides a method for preparing the above-mentioned substituted benzoic acid trifluoroalkylthioalkylthioester derivative, comprising the following steps:
  • step (2) dissolving the target product obtained in step (1) in an organic solvent, adding EDC ⁇ HCl, substituted benzoic acid and DMAP, reacting at room temperature, detecting the reaction end point by TLC, and separating and purifying the reaction product after the reaction is completed to obtain the substituted benzoic acid trifluoroalkylthioalkylthioester derivative.
  • the thiol is a dithiol having 1 to 10 carbon atoms.
  • the molar ratio of NaH to thiol is 1 to 2:1; the molar ratio of the bromotrifluoroalkyl compound to thiol is 1:1; and the molar ratio of TBAI to thiol is 0.1 to 1:1.
  • the substituted benzoic acid includes 2,3-dihydroxybenzoic acid, 2,3-diacetoxybenzoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 2-acetoxybenzoic acid or 3-acetoxybenzoic acid.
  • the molar ratio of EDC ⁇ HCl to thiol is 1 to 4:1; the molar ratio of substituted benzoic acid to thiol is 1 to 10:1; and the molar ratio of DMAP to thiol is 0.1 to 4:1.
  • the present invention also provides the use of the above-mentioned substituted benzoic acid trifluoroalkyl thioalkyl thioester derivatives in the preparation of drugs, health products or foods for preventing and/or treating inflammation.
  • the substituted benzoic acid trifluoroalkyl thioalkyl thioester derivatives of the present invention have significant anti-inflammatory activity in the in vitro screening model BV-2 cells, and can reduce the excessive activation of microglia and astrocytes.
  • the thioester derivatives can be used as active ingredients, and pharmaceutically acceptable carriers, diluents, etc. are added to prepare drugs for preventing and treating inflammation-related diseases.
  • the present invention also provides the use of the above-mentioned substituted benzoic acid trifluoroalkyl thioalkyl thioester derivatives in neuroprotective drugs, health products or foods.
  • the substituted benzoic acid trifluoroalkyl thioalkyl thioester derivatives of the present invention have the effect of reducing neuronal damage and death, and can be used for the preparation of neuroprotective drugs by adding pharmaceutically acceptable carriers, diluents, etc.
  • the present invention also provides the use of the above-mentioned substituted benzoic acid trifluoroalkyl thioalkyl thioester derivative in the preparation of a drug, health product or food for preventing and/or treating neurodegenerative diseases.
  • the substituted benzoic acid trifluoroalkyl thioalkyl thioester derivative of the present invention can be used to prevent and/or treat neurodegenerative diseases, especially Alzheimer's disease, etc.
  • the present invention also provides the use of the above-mentioned substituted benzoic acid trifluoroalkylthioalkyl thioester derivatives in the preparation of anti-aging drugs, health products or foods for prevention and/or treatment.
  • the substituted benzoic acid trifluoroalkylthioalkyl thioester derivatives of the present invention have significant activity in alleviating the generation of aging markers in the senescent PC12 cells induced by etoposide, an in vitro screening model of cell senescence.
  • An effective dose of the substituted benzoic acid trifluoroalkylthioalkyl thioester derivative can be used as an active ingredient, and a pharmaceutically acceptable carrier, diluent, etc. are added to prepare drugs for preventing and alleviating aging and aging-related diseases.
  • the present invention also provides the use of the above-mentioned substituted benzoic acid trifluoroalkyl sulfonated alkyl thioester derivative in the preparation of a drug, health product or food for preventing and/or treating hair loss.
  • the substituted benzoic acid trifluoroalkyl sulfonated alkyl thioester derivative of the present invention can achieve a hair growth effect similar to that of minoxidil at a dosage several times lower than that of minoxidil.
  • the substituted benzoic acid trifluoroalkyl sulfonated alkyl thioester derivative is used as an active ingredient, and a pharmaceutically acceptable carrier, diluent, etc. are added to prepare a drug related to preventing and/or treating hair loss.
  • the substituted benzoic acid trifluoroalkylthioalkylthioester derivative is administered by skin application at an amount of 0.25 times that of minoxidil to achieve a hair growth effect similar to that of minoxidil.
  • 0.50% of the compound 3 in the embodiment of the present invention and 2.0% of the minoxidil group have similar hair growth length and density.
  • the oral dosage of the substituted benzoic acid trifluoroalkylthioalkylthioester derivative is 1 to 25 mg/kg body weight, where the body weight refers to human body weight.
  • the present invention provides a pharmaceutical composition, health product or food for neuroprotection, prevention and/or treatment of inflammation and neurodegenerative diseases.
  • the pharmaceutical composition, health product or food contains the substituted benzoic acid trifluoroalkylthioalkylthioester derivative.
  • the present invention also provides an anti-aging and hair loss prevention and/or treatment product, wherein the anti-aging and hair loss prevention and/or treatment product comprises the substituted benzoic acid trifluoroalkylthioalkylthioester derivative according to claim 1.
  • the product of the present invention is an anti-aging and hair loss prevention and/or treatment drug, wherein the anti-aging, hair loss prevention and/or treatment drug contains the above-mentioned substituted benzoic acid trifluoroalkylthioalkylthioester derivative as an active ingredient.
  • the product of the present invention is an anti-aging and hair loss prevention and/or treatment food or health product, wherein the food or health product is composed of the above-mentioned substituted benzoic acid trifluoroalkylthioalkylthioester derivative and a carrier acceptable to the food or health product.
  • the product of the present invention is a toiletries for preventing and/or treating hair loss, wherein the toiletries are composed of the above-mentioned substituted benzoic acid trifluoroalkylthioalkylthioester derivative and an acceptable carrier in the toiletries.
  • the pharmaceutically acceptable carrier refers to conventional drug carriers in the pharmaceutical field, including fillers such as sucrose, starch, microcrystalline cellulose, inorganic salts, etc.; binders such as cellulose derivatives, starch slurry, povidone, gelatin, etc.; wetting agents such as distilled water, ethanol, etc.; lubricants such as magnesium stearate, micropowder silica gel, polyethylene glycols, etc.; absorption enhancers such as polysorbate, lecithin, etc., surfactant fatty acids such as sorbitan, poloxamer, etc.
  • other adjuvants such as sweeteners, flavoring agents, etc. can also be added to the pharmaceutical composition.
  • Figure 2 shows the effects of the substituted benzoic acid trifluoroalkylthioalkylthioester derivatives prepared in Example 3 on the activity of microglia and astrocytes in the cerebral cortex and hippocampus of mice fed a high-fat diet, and the expression of the inflammation-related indicator inducible nitric oxide synthase (INOS) protein, wherein Figure 2A-B shows the effects on the activity of microglia in the cerebral cortex and hippocampus; Figure 2C-D shows the effects on the activity of astrocytes in the cerebral cortex and hippocampus; Figure 2E-F shows the effects on the expression of INOS protein in the cerebral cortex and hippocampus.
  • IOS inflammation-related indicator inducible nitric oxide synthase
  • Figure 7 shows the effects of compound 3 on the hair loss area, hair growth length and hair growth density of aged mice, wherein Figure 7A shows the effect on the percentage of hair loss area of aged mice, Figure 7B shows the effect on the hair length of hair loss rats, and Figure 7C shows the effect on the hair growth density of hair loss rats.
  • 1,6-hexanedithiol (301.0 mg, 2.0 mmol) was used to prepare substituted benzoic acid trifluoroalkylthioalkylthioester derivatives.
  • the eluent used for ODS open column purification was MeOH/H 2 O with a volume ratio of 80:20. The rest was the same as in Example 1.
  • the obtained product was recorded as Compound 3.
  • 1,8-octanedithiol 357.0 mg, 2.0 mmol
  • substituted benzoic acid trifluoroalkylthioalkylthioester derivatives 357.0 mg, 2.0 mmol
  • the rest was the same as in Example 3.
  • the obtained product was recorded as Compound 4.
  • 1,10-decanedithiol (413.0 mg, 2.0 mmol) was used to prepare substituted benzoic acid trifluoroalkylthioalkylthioester derivatives, and the rest was the same as in Example 3.
  • the obtained product was recorded as Compound 5.
  • this example performs an acetylation reaction on compound 3 based on the prepared compound 3 to synthesize the prodrug compound 6 of compound 3.
  • acetic anhydride (0.47 mL, 5.0 mmol) is added to an anhydrous pyridine solution (1.0 mL) of compound 3 (200.0 mg, 0.5 mmol) at room temperature, the reaction is stirred and then quenched with 1N HCl solution, vacuum concentrated, the concentrate is extracted with EtOAc, the organic phase is dried over Na 2 SO 4 , filtered and concentrated, and the rest is the same as Example 3, and the obtained product is recorded as compound 6.

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

Abstract

Sont divulgués dans la présente invention un dérivé de benzothioate de trifluoroalkyle thioalkyle substitué, son procédé de préparation et son utilisation. Le dérivé présente une structure telle que représentée dans une formule (I). Est en outre divulgué dans la présente invention le procédé de préparation du dérivé de benzothioate de trifluoroalkyle thioalkyle substitué susmentionné. Le dérivé de benzothioate de trifluoroalkyle thioalkyle substitué de la présente invention présente une activité anti-inflammatoire et une activité neuroprotectrice, et peut être utilisé dans la préparation et l'application de produits pharmaceutiques, d'aliments ou de produits de soins de santé liés à une anti-inflammation, une neuroprotection et des maladies anti-neurodégénératives. Le dérivé de benzothioate de trifluoroalkyle thioalkyle substitué peut également retarder le processus de vieillissement, prévenir des maladies liées au vieillissement, présente également l'effet d'augmenter la vitesse et la densité de la pousse des cheveux, et peut ainsi être utilisé pour développer des produits pharmaceutiques, des aliments, des produits de soins de santé ou des produits de soins personnels, etc., dirigés contre le vieillissement, et la prévention et/ou le traitement de l'alopécie.
PCT/CN2024/140882 2023-12-22 2024-12-20 Dérivé de benzothioate de trifluoroalkyle thioalkyle substitué, son procédé de préparation et son utilisation Pending WO2025131037A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN202311779160.6 2023-12-22
CN202311779160 2023-12-22
CN202311785388 2023-12-22
CN202311785388.6 2023-12-22
CN202410086203.0A CN120192256A (zh) 2023-12-22 2024-01-22 一种取代苯甲酸三氟烷基硫代烷基硫酯衍生物及其制备方法与应用
CN202410086203.0 2024-01-22
CN202410087623.0 2024-01-22
CN202410087623.0A CN120189404A (zh) 2023-12-22 2024-01-22 取代苯甲酸三氟烷基硫代烷基硫酯衍生物在预防和/或治疗抗衰老以及抗脱发中的应用

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WO2025131037A1 true WO2025131037A1 (fr) 2025-06-26

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774922A (zh) * 2010-01-29 2010-07-14 浙江大学 2,3-二羟基苯甲酸酯类化合物及制备和应用
CN101817761A (zh) * 2010-01-29 2010-09-01 浙江大学 苯甲酸酯类衍生物及制备方法和应用
CN105085348A (zh) * 2014-05-20 2015-11-25 浙江大学 一种苯甲酸硫酯类化合物及其应用
CN116836096A (zh) * 2023-06-27 2023-10-03 浙江大学 一类硫代苯甲酸酯类化合物及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774922A (zh) * 2010-01-29 2010-07-14 浙江大学 2,3-二羟基苯甲酸酯类化合物及制备和应用
CN101817761A (zh) * 2010-01-29 2010-09-01 浙江大学 苯甲酸酯类衍生物及制备方法和应用
CN105085348A (zh) * 2014-05-20 2015-11-25 浙江大学 一种苯甲酸硫酯类化合物及其应用
CN116836096A (zh) * 2023-06-27 2023-10-03 浙江大学 一类硫代苯甲酸酯类化合物及其制备方法和应用

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