WO2021238587A1 - Dérivé d'oxathiazine micromoléculaire et son utilisation - Google Patents

Dérivé d'oxathiazine micromoléculaire et son utilisation Download PDF

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WO2021238587A1
WO2021238587A1 PCT/CN2021/091631 CN2021091631W WO2021238587A1 WO 2021238587 A1 WO2021238587 A1 WO 2021238587A1 CN 2021091631 W CN2021091631 W CN 2021091631W WO 2021238587 A1 WO2021238587 A1 WO 2021238587A1
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李涛
漆学宇
于雪莉
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四川大学华西医院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to the technical field of innovative chemical medicines, in particular to a small molecule oxthiazide derivative and its application.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
  • G1uR1 ⁇ 4 four core subunits G1uR1 ⁇ 4, which mediate the main rapid excitatory transmission of the central nervous system, promote neurodevelopment and highlight plasticity, and participate in a variety of neuronal activity processes. It is one of the most important and neurological processes in the field of innovative chemical drugs. Important targets related to system diseases.
  • each AMPA receptor subunit contains two domains: the amino-terminal domain (ATD) involved in subunit assembly and the ligand binding domain (LBD) that provides glutamate binding.
  • ATD amino-terminal domain
  • LBD ligand binding domain
  • the AMPA receptor positive allosteric modulator has a different binding site from the AMPA receptor agonist, which can make the conformation of the agonist (such as the endogenous neurotransmitter glutamate) bound to the receptor more stable, thereby Reduce receptor inactivation rate and inhibit receptor desensitization, so that the function of AMPA receptor can be enhanced. Therefore, positive allosteric modulators of AMPA receptors will not be excessively stimulated and will not cause neurotoxic damage; compared to agonists that directly act on AMPA receptors, positive allosteric modulators are more Advantage.
  • AMPA receptor is an important drug target.
  • Basic clinical studies have shown that AMPA receptor positive allosteric modulators have neuroprotective effects on brain damage, improve cognition, and regulate depression-like behaviors to achieve rapid antidepressant effects.
  • An effective strategy for the treatment of neuropsychiatric diseases The existing research results point out the direction for the design of AMPA receptor positive allosteric modulators, but most of them are in the preclinical research stage or clinical trial stage. With the gradual deepening of structure-activity relationship research, it will better help people find and discover more positive allosteric modulators of AMPA receptors, and lay the foundation for the development of innovative drugs targeting AMPA receptors.
  • the purpose of the present invention is to provide a novel structure and strong activity of small molecule oxathiazine derivatives.
  • Another object of the present invention is to provide specific applications of the aforementioned small molecule oxathiazine derivatives as positive allosteric modulators of AMPA receptors.
  • Another object of the present invention lies in the specific application of the positive allosteric modulator based on the AMPA receptor provided above in the preparation of drugs for the treatment of neuropsychiatric diseases.
  • the present invention provides a small molecule oxathiazine derivative, the general formula of which is as follows:
  • X is an independent ether bond, halogen
  • R1 is independent Methyl, H or not present
  • A is an independent benzene ring, naphthalene ring, isoxazole ring, phenanthrene ring, indole ring, indazole ring, pyrazole ring, pyridine ring, isoquinoline ring, quinoline ring, fluorene ring;
  • R 2 , R 3 , R 4 , R 12 , and R 13 are independently H, halogen, methyl, trifluoromethyl, cyano, neobutyl, ester group, Peptide bond, F 3 C—, F 2 HC—, F 3 CO—, O 2 S—R 5 , Benzene ring, naphthalene ring, Carbazole ring, Or does not exist
  • R 5 is independent isopropyl and methyl
  • R 6 is an independent ether bond, n-propyl, isopropyl, ethyl, benzene ring, benzyl, methyl;
  • R 7 is independent halogen, F 3 C—, F 2 HC—, neobutyl, cyano, H, methyl;
  • R 8 and R 9 are independent halogen, H, and ether bonds
  • R 10 is an independent H, halogen, or ether bond
  • R 11 is independent isopropyl, methyl, F 3 C—;
  • R 14 is a methyl group or a benzene ring.
  • the present invention also provides a positive allosteric modulator of AMPA receptor, a biopharmaceutical acceptable salt, polymorph, and solvate with the above-mentioned small molecule oxathiazine derivatives as the main active ingredient.
  • the present invention also provides a medicament for treating neuropsychiatric diseases, which takes the above-mentioned positive allosteric modulator of AMPA receptor as the main component, and adds a pharmaceutically acceptable drug that is non-toxic and non-inert to humans and animals.
  • Prodrugs or pharmaceutical compositions prepared with auxiliary components of carriers and/or excipients.
  • the pharmaceutical carriers or excipients are one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical products adjuvants.
  • the pharmaceutical composition is prepared into various dosage forms by methods recognized in the pharmaceutical and food fields: sprays, aerosols, liquid preparations or solid preparations; the liquid preparations include injections, suspensions, emulsions, solutions or syrups
  • the solid preparation includes tablets, capsules, granules or granules.
  • the neuropsychiatric diseases treated by the drug include schizophrenia, Alzheimer's disease, Parkinson's disease, depression, and bipolar disorder.
  • the administration route of the drug is oral, sublingual administration or mucosal dialysis; the injection includes intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.
  • the present invention has the following advantages and beneficial effects:
  • the present invention synthesizes a new type of compound, which can be used as a positive allosteric modulator of AMPA receptors.
  • the conformation after the acid is combined with the receptor is more stable, thereby reducing the receptor inactivation rate and inhibiting the receptor desensitization, so that the function of the AMPA receptor can be enhanced.
  • Figure 1 is a curve diagram of the EC 50 test result of the compound LT-1 calcium influx in the present invention
  • Figure 2 is a curve diagram of the EC 50 test result of the compound LT-2 calcium influx in the present invention
  • Figure 3 is a curve diagram of the EC 50 test result of the compound LT-9 calcium influx in the present invention.
  • Figure 4 is a curve diagram of the EC 50 test result of the compound LT-41 calcium influx in the present invention
  • Figure 5 is a curve diagram of the EC 50 test result of the compound LT-47 calcium influx in the present invention.
  • Figure 6 is a curve diagram of the EC 50 test result of the compound LT-68 calcium influx in the present invention.
  • Figure 7 is a curve diagram of the EC 50 test result of the compound LT-72 calcium influx in the present invention.
  • Figure 8 is a curve diagram of the EC 50 test result of the compound LT-81 calcium influx in the present invention.
  • Figure 9 is a graph showing the detection result of compound LT-41 in the present invention on rat brain-derived neurotrophic factor
  • FIG. 10 is a graph of the new object recognition test results of experimental mice under the influence of compound LT-41 in the present invention.
  • Figure 11 is a diagram showing the Y-maze test results of experimental rats under the influence of compound LT-41 in the present invention.
  • Figure 12 is a graph showing the results of a forced swimming test of experimental mice under the influence of compound LT-72 in the present invention.
  • the specific preparation method is as follows:
  • A01b (2.62g, 10mmol) was dispersed in a 50ml MeOH solvent system, sodium borohydride (380mg, 10.6mmol) was added in batches at room temperature, and after the addition, stirring was continued at room temperature until the reaction of the raw material A01b was complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate.
  • This example discloses the compound: 8-(4-tolyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (LT-2).
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “p-tolueneboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “p-tert-butylphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “p-cyanophenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “p-trifluoromethylphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “p-trifluoromethoxyphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “3-fluoro-4-methoxyphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “4-isopropylsulfonylphenylboronic acid”.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • A23b (213mg, 1mmol) was dispersed in 5ml MeOH solvent system, sodium borohydride (38mg, 1mmol) was added in batches at room temperature, and after the addition, stirring was continued at room temperature until the reaction of the raw material A23b was complete. Quench with saturated ammonium chloride solution (2ml) and transfer to a separatory funnel with 3mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 ⁇ 3 mL ethyl acetate. The combined organic layer was washed sequentially with 2 ⁇ 2 mL of H2O and 1 ⁇ 2 mL of saturated NaCl aqueous solution, dried over Na2SO4, and concentrated under reduced pressure. Purified by silica gel chromatography, 8-methoxy-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (LT-23 ).
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “4-propoxyphenylboronic acid”.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “6-methoxynaphthalene-2-boronic acid”.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • Disperse A02b (2.62g, 10mmol) in a 50ml MeOH solvent system, add sodium borohydride (380mg, 10.6mmol) in batches at room temperature, and continue stirring at room temperature until the reaction of the raw material A02b is complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate. The combined organic layer was washed sequentially with 2 ⁇ 20 mL of H2O and 1 ⁇ 20 mL of saturated aqueous NaCl solution, dried over Na2SO4, and concentrated under reduced pressure.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • A03b (2.62g, 10mmol) was dispersed in 50ml MeOH solvent system, sodium borohydride (380mg, 10.6mmol) was added in batches at room temperature, and after the addition, stirring was continued at room temperature until the reaction of the raw material A03b was complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • A04b (2.62g, 10mmol) was dispersed in 50ml MeOH solvent system, sodium borohydride (380mg, 10.6mmol) was added in batches at room temperature, and after the addition, stirring was continued at room temperature until the reaction of the raw material A04b was complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “3-phenoxyphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “4-biphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “9-phenanthreneboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “5-indoleboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “3-fluoro4-biphenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “6-ethoxy-2-naphthaleneboronic acid”.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • the C01c (320mg, 1mmol) were dispersed in 10ml of dichloromethane, and then BBr 3 was slowly 1ml 1M tetrahydrofuran under nitrogen.
  • the reaction system is stirred and slowly rises to room temperature until the reaction is complete. After the reaction, it was quenched by adding ammonium chloride aqueous solution, and transferred to a separatory funnel with 20 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 ⁇ 20 mL ethyl acetate.
  • Disperse C01e (74mg, 0.2mmol) in 5ml MeOH solvent system, add sodium borohydride (10mg, 0.2mmol) in batches at room temperature, and continue to stir at room temperature until the reaction of the raw material C01e is complete. Quench with saturated ammonium chloride solution (10 ml) and transfer to a separatory funnel with 10 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 ⁇ 10 mL ethyl acetate. The combined organic layer was washed sequentially with 2 ⁇ 10 mL of H 2 O and 1 ⁇ 10 mL of saturated NaCl aqueous solution, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “4-(1-naphthyl)phenylboronic acid”.
  • the synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid” with “3-biphenylboronic acid”.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • Disperse A01b (2.62g, 10mmol) in a 50ml MeOH solvent system, add sodium borohydride (380mg, 10.6mmol) in batches at room temperature, and continue stirring at room temperature until the reaction of the raw material A01b is complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate. The combined organic layer was washed sequentially with 2 ⁇ 20 mL of H2O and 1 ⁇ 20 mL of saturated aqueous NaCl solution, dried over Na2SO4, and concentrated under reduced pressure.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • Disperse A01b (2.62g, 10mmol) in a 50ml MeOH solvent system, add sodium borohydride (380mg, 10.6mmol) in batches at room temperature, and continue stirring at room temperature until the reaction of the raw material A01b is complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate. The combined organic layer was washed sequentially with 2 ⁇ 20 mL of H 2 O and 1 ⁇ 20 mL of saturated NaCl aqueous solution, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • A47e (62mg, 0.2mmol), p-methoxyphenylboronic acid A33f (37mg, 0.24mmol), potassium phosphate (85mg, 0.4mmol), Pd(OAc) 2 (10mg, 0.02mmol), X-PHOS (20mg, 0.04mmol) dioxane (4ml) and H 2 O (1ml) were sequentially added to a 25ml two-necked flask, and stirred at 90°C for 10 hours under argon protection. After the completion of the reaction detected by TLC, 20 ml of saturated brine was added, and extraction was performed twice with ethyl acetate (20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product LT-82 with a yield of 56%.
  • the synthetic route is as follows:
  • the specific preparation method is as follows:
  • A01b (2.62g, 10mmol) was dispersed in a 50ml MeOH solvent system, sodium borohydride (380mg, 10.6mmol) was added in batches at room temperature, and after the addition, stirring was continued at room temperature until the reaction of the raw material A01b was complete. Quench with saturated ammonium chloride solution (20 ml) and transfer to a separatory funnel with 30 mL ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2 x 30 mL ethyl acetate.
  • rat primary neurons were taken from SD rats at the 19th day of pregnancy, and the embryos were placed in pre-cooled HBSS buffer. Take out the fetal rat brain under a microscope, remove the meninges, separate the hippocampus, use iris scissors to cut the brain tissue into a 1mm 3 size paste, add 10% FBS-containing DMEM culture solution, blow to prepare a single cell suspension, and then 5 /mL was inoculated on the PDL-coated culture plate and placed in the incubator for culture. After 6h, the medium was changed, and the culture was continued with Neurobasal+2%B27+2mM glutamine medium, and the medium was changed every 2 days.
  • a fluorescence microplate reader was used to detect the relative increase in intracellular Ca 2+ levels induced by the compound in the presence and absence of 5 ⁇ M s-AMPA for 15 minutes.
  • the activity of the compound is defined as the fluorescence intensity integrated during the entire measurement period. Intensity 0% is defined as the activity in the presence of only 5 ⁇ M s-AMPA, and intensity 100% is defined as the activity in the presence of 5 ⁇ M s-AMPA and 10 ⁇ M TAK-137.
  • oxathiazine derivatives can promote the influx of calcium ions in primary neurons in a dose-dependent manner, and show positive regulatory activity on AMPA receptors.
  • This example focuses on the detection of rat brain-derived neurotrophic factor (BDNF) for compound LT-41.
  • BDNF brain-derived neurotrophic factor
  • the specific detection process is as follows:
  • the primary neurons were grown in a 6-well plate and incubated in the incubator for five days.
  • the endogenous agonist 1 ⁇ M s-AMPA was added, and then the test compound 8-(4-phenoxyphenyl) with a solubility of 2.5 ⁇ M was added.
  • -3,4-Dihydrobenzo[e][1,2,3]oxthiazide 2,2-dioxide LT-41 incubate, centrifuge to collect the supernatant after 24h, use rat brain-derived neurotrophic factor (BDNF) enzyme-linked immunosorbent assay kit detection.
  • BDNF brain-derived neurotrophic factor
  • Sprague-Dawley rat male, 200-250g; C57 mouse, male, 22-25g; purchased from Chengdu Dashuo Experimental Animal Co., Ltd., raised in the animal laboratory of our unit. Feeding conditions: temperature 25 ⁇ 1°C, humidity 50-60%, 12/12h circadian rhythm, standard animal feeding and feeding, adapt to the environment in the animal laboratory for 7 days before the experiment, eat and drink freely.
  • test compound was added to the final volume of 1% DMSO, 4% Tween 80 and 95% normal saline, and vortexed or sonicated to mix well.
  • Phencyclidine (PCP) was dissolved in physiological saline (0.9% sodium chloride) in physiological saline.
  • Rats and mice were injected intraperitoneally, and the administration volume of all drugs was 5ml/kg and 10ml/kg respectively.
  • Dosage regimen normal rats and mice are given intraperitoneal physiological saline; model rats and mice are given intraperitoneal PCP (10mg/kg); treated rats and mice are given intraperitoneal administration of LT-41 (3mg/kg) for half an hour and then intraperitoneal PCP (10mg/kg). kg); LT-72 (0.1mg/kg) was administered intraperitoneally to treat mice.
  • the experimental device is a transparent organic plastic drum with a diameter of 15 cm and a height of 25 cm.
  • the water depth is 15 cm and the water temperature is controlled at 25 ⁇ 1°C.
  • the total test is 6 minutes, the first two minutes are the adaptation process, and the immobility time of the mouse is recorded for the next four minutes.
  • the definition of immobility of a mouse is: a mouse floating head up on the water surface or doing a small swim necessary to keep its head floating on the water surface.

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Abstract

Dérivé d'oxathiazine micromoléculaire qui appartient au domaine des médicaments de synthèse organique et dont la formule générale est présentée ci-dessous : le dérivé d'oxathiazine micromoléculaire peut être utilisé en tant que modulateur allostérique positif d'un récepteur AMPA, ce qui prouve que le composé peut réguler positivement le récepteur AMPA, de sorte que la conformation, après qu'un agoniste (tel qu'un acide glutamique de neurotransmetteur endogène) est combiné avec le récepteur, est plus stable, ce qui permet de réduire le taux de désactivation du récepteur, d'inhiber la désensibilisation du récepteur, et d'améliorer la fonction du récepteur AMPA.
PCT/CN2021/091631 2020-05-29 2021-04-30 Dérivé d'oxathiazine micromoléculaire et son utilisation WO2021238587A1 (fr)

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CN115232090A (zh) * 2022-07-19 2022-10-25 杭州市第七人民医院 6位取代二氢苯并[e][1,2,3]噁噻嗪2,2-二氧化类化合物及其制备与应用

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CN111559990B (zh) * 2020-05-29 2021-03-09 四川大学华西医院 一种小分子噁噻嗪类衍生物及其应用
CN114031630A (zh) * 2021-11-20 2022-02-11 福州大学 一种螺环噻吩磺酰胺类化合物的合成方法

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