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WO2022267470A1 - Inhibiteur de seh ou composition pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée - Google Patents

Inhibiteur de seh ou composition pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée Download PDF

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WO2022267470A1
WO2022267470A1 PCT/CN2022/073959 CN2022073959W WO2022267470A1 WO 2022267470 A1 WO2022267470 A1 WO 2022267470A1 CN 2022073959 W CN2022073959 W CN 2022073959W WO 2022267470 A1 WO2022267470 A1 WO 2022267470A1
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present
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陈国良
杜芳瑜
刘中博
曹若琳
陈露
傅扬
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • 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
    • A61P25/28—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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the technical field of medicine, in particular to an sEH inhibitor or a pharmaceutically acceptable composition thereof, a preparation method and application thereof.
  • Soluble epoxide hydrolase is ubiquitous in mammalian tissues, especially in liver, kidney, lung, intestinal tract and blood vessels.
  • sEH inhibitors can stabilize endogenous epoxy fatty acids (EETs) with a wide range of physiological activities.
  • EETs are a class of endogenous lipid epoxy compounds with strong biological activities.
  • Anti-inflammatory, analgesic, anti-apoptotic, anti-fibrosis, anti-ischemic effects, and at the same time show protective effects on the heart, lungs, kidneys, brain and other organs. Therefore, sEH inhibitors have received extensive attention.
  • the central pharmacophores of sEH inhibitors include amides, carbamates, and ureas.
  • the residence time (t1/2) of the sEH inhibitor on the target enzyme is one of the most important parameters affecting the efficacy in vivo. Inhibitors with a long residence time have a longer action time on the target enzyme and a longer transformation effect in vivo.
  • the aforementioned sEH inhibitors have a short residence time and poor efficacy in vivo.
  • the object of the present invention is to provide a kind of sEH inhibitor or its pharmaceutically acceptable composition and its preparation method and application, the sEH inhibitor provided by the present invention has a long residence time in vivo, and the medicine containing sEH inhibitor has great effect on sEH-mediated The treatment effect of the disease is excellent.
  • the present invention provides a sEH inhibitor or a pharmaceutically acceptable derivative or composition thereof, the sEH inhibitor has the structure shown in formula I:
  • the pharmaceutically acceptable derivatives include deuterated products or hydrates
  • composition in the pharmaceutically acceptable composition includes one or more of deuterium compounds and hydrates.
  • the deuterated substance is that the carbamoyl group, the piperidine ring and the hydrogen atom on the 3,5-dimethyl group in formula I are replaced by deuterium.
  • the hydrate is 1-5 hydrate.
  • the present invention provides a preparation method of the sEH inhibitor described in the above technical scheme, comprising the following steps:
  • chlorination reaction is carried out to obtain an acid chloride intermediate; the acid chloride intermediate, ammonia solution, ice and soluble acid chloride intermediate solvent are mixed for acylation Reaction, obtains the sEH inhibitor with the structure shown in formula I;
  • the chlorination reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
  • the catalyst includes a Lewis acid and/or a Lewis base;
  • the Lewis acid includes one or more of zinc chloride, aluminum trichloride, boron trifluoride, iron trichloride and tin chloride;
  • the Lewis base includes one or more of N,N-dimethylformamide (DMF), pyridine and 4-dimethylaminopyridine.
  • DMF N,N-dimethylformamide
  • the mass concentration of the ammonia solution is 5-28%;
  • the solvents in the ammonia solution include water, alcohol solvents, ether solvents, chlorinated hydrocarbon solvents, ester solvents, heterocyclic solvents, nitriles solvents or ketones.
  • the molar ratio of the compound II, the chlorination reagent and the ammonia in the ammonia solution is 1:1.05-2:5-20.
  • the temperature of the chlorination reaction is 0-80°C, and the time is 0.5-6h;
  • the temperature of the acylation reaction is -10-0° C., and the time is 2-10 hours.
  • the preparation method of the compound II comprises the following steps:
  • step (1) the molar ratio of the compound 1 to ethyl (S)-piperidine-3-carboxylate is 1:1-1.5; the temperature of the acylation reaction is 0-40°C, and the time 0.1 ⁇ 6h;
  • the metal reducing agent includes iron and/or zinc; the molar ratio of the compound 2 and the metal reducing agent is 1:3.3-5; the temperature of the reduction reaction is 50-100°C, and the time is 0.1 ⁇ 6h;
  • step (3) the molar ratio of compound 3, solid phosgene and memantine is 1:0.34 ⁇ 1:1 ⁇ 1.5; the temperature of the nucleophilic substitution-elimination reaction is -10 ⁇ 30°C, and the time is 0.5 ⁇ 4h; the temperature of the nucleophilic substitution reaction is -10 ⁇ 30°C, and the time is 0.5 ⁇ 4h.
  • the organic base in the step (1) and step (3) independently includes one or more of triethylamine, N,N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine kind.
  • the acidic reagent includes one or more of ammonium chloride, acetic acid and hydrochloric acid.
  • step (4) the hydrolysis is carried out in the presence of an inorganic base;
  • the inorganic base includes hydroxide and/or carbonate;
  • the molar ratio of the compound 4 to the inorganic base is 1:3-20;
  • the temperature of the hydrolysis reaction is 5-100° C., and the time is 0.5-5 hours.
  • the preparation method of compound 1 is to mix 3-fluoro-4-nitrobenzoic acid, a catalyst, a chlorination reagent and a soluble 3-fluoro-4-nitrobenzoic acid solvent, and then perform a chlorination reaction to obtain the compound 1.
  • the catalyst includes a Lewis acid and/or a Lewis base;
  • the Lewis acid includes one or more of zinc chloride, aluminum trichloride, boron trifluoride, iron trichloride and tin chloride;
  • the Lewis base includes one or more of N,N-dimethylformamide, pyridine and 4-dimethylaminopyridine;
  • the chlorination reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride;
  • the molar ratio of the 3-fluoro-4-nitrobenzoic acid, the catalyst and the chlorination reagent is 1:1.05 ⁇ 3:0.001 ⁇ 0.2;
  • the temperature of the chlorination reaction is 0-80°C, and the time is 0.1-6h.
  • the present invention provides the application of the sEH inhibitor described in the above technical scheme or its pharmaceutically acceptable derivative or composition or the sEH inhibitor prepared by the preparation method described in the above technical scheme in the preparation of medicines for treating sEH-mediated diseases .
  • the present invention provides the application of the sEH inhibitor described in the above technical scheme or its pharmaceutically acceptable derivative or composition or the sEH inhibitor prepared by the preparation method described in the above technical scheme in the treatment of sEH-mediated diseases.
  • the sEH-mediated disease includes pain, inflammation, cardiovascular disease, neurodegenerative disease, metabolic disease or renal disease.
  • the pain includes neuropathic pain, inflammatory pain or cancer pain;
  • the inflammation includes sepsis, neuroinflammation, inflammatory bowel disease, chronic peptic ulcer or arthritis;
  • the cardiovascular disease includes hypertension, cardiomyopathy, stroke or atherosclerosis;
  • the neurodegenerative disease includes Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis;
  • Such metabolic diseases include diabetes or gout.
  • the dosage form of the sEH inhibitor includes tablet, capsule, oral tincture ointment, oral pill, oral granule, oral powder, oral powder, external tincture, external ointment, external patch, external powder, external paint, suppository or injections.
  • the tablet includes enteric-coated tablet, coated tablet, film-coated tablet, sugar-coated tablet, extract tablet, dispersible tablet, scored tablet, sustained-release tablet, sustained-release coated tablet or controlled-release tablet.
  • the effective dose of the sEH inhibitor is 10-500 mg.
  • the administration of the sEH inhibitor includes oral administration, injection or infusion.
  • the site of administration of the sEH inhibitor includes parenteral, intraperitoneal, transmucosal, transdermal, rectal or local; the parenteral includes subcutaneous, intramuscular, intravenous, intraarticular or intramedullary; Such topical includes the skin, sublingually or intraocularly.
  • the present invention provides a sEH inhibitor or a pharmaceutically acceptable derivative or composition thereof, the sEH inhibitor has a structure shown in formula I, and its chemical name is (S)-1-(4- ⁇ 3- [(1r,3R,5S,7S)-3,5-Dimethyladamantan-1-yl]ureido ⁇ -3-fluorobenzoyl)piperidine-3-carboxamide.
  • Opioid pain drugs can not only bind to peripheral nerve opioid receptors, but also can bind to opioid receptors in sensory neurons located in the dorsal horn of the spinal cord (second layer) in the human body, and can also inhibit the activity of substance P.
  • Opioids can also act on the pain central system in tissues such as the brain and brainstem of the human body, thereby exerting a strong downward pain inhibitory effect.
  • Non-steroidal anti-inflammatory drugs mainly inhibit cyclooxygenase, reduce the production of prostaglandins, inflammatory mediators, and produce anti-inflammatory, analgesic, and antipyretic effects.
  • Ion channels play a key role in pain generation and pain processing, and are the main targets for regulating neuropathic pain.
  • Antiepileptic drugs mainly act on ion channels, reduce neuronal excitability, increase membrane stability and regulate neuronal hyperactivity. Discharge, thereby reducing pain.
  • the sEH inhibitor provided by the present invention can stabilize the endogenous substance epoxy fatty acid (EETs) with a wide range of physiological activities, has a strong inhibitory effect on human recombinant sEH, and can regulate the production of various proinflammatory cytokines, Reducing endoplasmic reticulum stress, preventing or reversing endothelial dysfunction, and stabilizing mitochondrial function can significantly relieve neuropathic pain through various mechanisms of action, which are completely different from opioid analgesics, non-steroidal anti-inflammatory drugs, antiepileptic drugs, etc. ;
  • the sEH inhibitor provided by the present invention can effectively avoid target-related adverse reactions.
  • the sEH inhibitor structure provided by the present invention does not contain free carboxyl groups, which can avoid adverse reactions such as gastrointestinal tract irritation caused by oral administration; moreover, the sEH inhibitor structure provided by the present invention contains fluorine
  • the atom can improve the metabolic stability of the compound; in addition, the 3,5-dimethyl group in the memantine structure can enhance the combination with sEH, and the metabolic stability is better than that of the adamantane structure. The residence time is longer.
  • the half-inhibitory concentration of the sEH inhibitor provided by the present invention to recombinant human sEH is at the nanomolar level; the half-life (t 1/2 ) in human and rat liver microsomes is 174min and 120min, respectively , long retention time in the body; after oral administration of 6g/kg in mice, no toxicity and adverse reactions were shown; after intravenous injection of 10mg/kg of sEH inhibitor in SD rats, after 5min, the plasma concentration of GL-B437 The peak value was 3342.73ng/L; the total exposure under the drug-time curve AUC 0-24h (the area under the drug-time curve within 24h) was 1832.11ng ⁇ h/L; the half-life was 6.25h.
  • the peak time was 38min
  • the total exposure under the drug-time curve AUC 0-24h was 2620.520ng h/L
  • the half-life was 5.179h
  • the absolute bioavailability of GL-B437 was 28.6 %.
  • the neuropathic pain model of rats it shows a strong analgesic effect, the onset of action is faster than gabapentin, and the analgesic effect after continuous administration is better than that of gabapentin, and the molar dosage is only one-sixth of gabapentin.
  • the sEH inhibitor provided by the present invention has a long retention time in the body and long efficacy in the body, and the medicine containing the sEH inhibitor has an excellent therapeutic effect on the disease mediated by sEH; moreover, the sEH inhibitor has small side effects and high bioavailability, The analgesic effect is excellent and the dosage is small.
  • the present invention provides a preparation method of the sEH inhibitor described in the above technical scheme or a pharmaceutically acceptable composition thereof.
  • the preparation method provided by the present invention has simple operation, high yield and is suitable for industrial production.
  • Fig. 1 is the drug-time curve after tail vein injection and gavage administration in Test Example 3;
  • Fig. 2 is the mouse body weight comparison result of control group and administration group in test example 4.
  • Fig. 3 is the comparison result of the paw contraction threshold in Test Example 5, wherein a is the comparison result of the paw contraction threshold between the control group and each administration group, and b is the comparison result of the paw contraction threshold between the control group and each administration group before administration;
  • Fig. 4 is the comparison result of the paw contraction threshold between the model group and each administration group in Test Example 5;
  • Figure 5 is the drug time-effect curve after the last administration in Test Example 5.
  • the present invention provides a sEH inhibitor or a pharmaceutically acceptable derivative or composition thereof, the sEH inhibitor has the structure shown in formula I:
  • the pharmaceutically acceptable composition includes one or more of deuterated compounds and hydrates, preferably includes pharmaceutically acceptable deuterated compounds and pharmaceutically acceptable hydrates.
  • the derivatives include deuteriums or hydrates.
  • the deuterium is preferably that the carbamoyl group, the piperidine ring and the hydrogen atom on the 3,5-dimethyl group in formula I are replaced by deuterium.
  • the pharmaceutically acceptable hydrate is preferably 1-5 hydrate.
  • the present invention provides a preparation method of the sEH inhibitor described in the above technical scheme, comprising the following steps:
  • the preparation method of compound II preferably includes the following steps:
  • the present invention mixes compound 1, (S)-piperidine-3-ethyl carboxylate, an organic base and a soluble compound 1 solvent to carry out acylation reaction to obtain compound 2 ((S)-1-(4-nitro- 3-fluorobenzoyl)piperidine-3-carboxylic acid ethyl ester).
  • the preparation method of the compound 1 (3-fluoro-4-nitrobenzoyl chloride) preferably comprises the following steps: 3-fluoro-4-nitrobenzoic acid, catalyst, chlorination reagent and soluble After mixing 3-fluoro-4-nitrobenzoic acid solvents, chlorination reaction was carried out to obtain compound 1 (3-fluoro-4-nitrobenzoyl chloride).
  • the catalyst preferably includes a Lewis acid and/or a Lewis base;
  • the Lewis acid preferably includes one of zinc chloride, aluminum trichloride, boron trifluoride, iron trichloride and tin chloride or several;
  • the Lewis base preferably includes one or more of N,N-dimethylformamide, pyridine and 4-dimethylaminopyridine.
  • the chlorination reagent preferably includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
  • the molar ratio of the 3-fluoro-4-nitrobenzoic acid, the catalyst and the chlorination reagent is preferably 1:1.05-3:0.001-0.2, more preferably 1:1.1-1.5:0.001-0.1 .
  • the soluble 3-fluoro-4-nitrobenzoic acid solvent preferably includes dichloromethane, chloroform, toluene, tetrahydrofuran or chlorination reagent; the soluble 3-fluoro-4-nitrobenzoic acid
  • the solvent is preferably a dry soluble 3-fluoro-4-nitrobenzoic acid solvent; the present invention has no special limitation on the amount of the soluble 3-fluoro-4-nitrobenzoic acid solvent, and 3-fluoro-4- Nitrobenzoic acid can be dissolved; in an embodiment of the present invention, the amount of the 3-fluoro-4-nitrobenzoic acid and 0.14mol of soluble 3-fluoro-4-nitrobenzoic acid solvent: 200mL.
  • the mixing sequence is preferably to mix 3-fluoro-4-nitrobenzoic acid, catalyst and partially soluble 3-fluoro-4-nitrobenzoic acid solvent to obtain a mixed solution; Mix with the remaining soluble 3-fluoro-4-nitrobenzoic acid solvent to obtain a 3-fluoro-4-nitrobenzoic acid solution; add the 3-fluoro-4-nitrobenzoic acid solution dropwise to the mixing In the solution;
  • the present invention has no special limitation on the amount of the partially soluble 3-fluoro-4-nitrobenzoic acid solvent, as long as the 3-fluoro-4-nitrobenzoic acid can be dissolved; in the embodiments of the present invention Among them, the ratio of the amount of the substance of the 3-fluoro-4-nitrobenzoic acid to the volume of the partially soluble 3-fluoro-4-nitrobenzoic acid solvent is preferably 0.14mol: 150mL;
  • the amount of 3-fluoro-4-nitrobenzoic acid solvent is not particularly limited, as long as the chlorinated reagent can be dissolved;
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the temperature of the chlorination reaction is preferably 0-80°C, more preferably 30-60°C; the time of the chlorination reaction is preferably 0.1-6h, more preferably 1-2h; the chlorine During the substitution reaction, 3-fluoro-4-nitrobenzoic acid reacts with a chlorination reagent to form compound 1.
  • the present invention preferably further includes concentrating the chlorination reaction system to a constant weight to obtain compound 1; the method of concentrating is preferably vacuum distillation.
  • the molar ratio of the compound 1 to ethyl (S)-piperidine-3-carboxylate is preferably 1:1-1.5, more preferably 1:1.2-1.3.
  • the organic base preferably includes one or more of triethylamine, N,N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine.
  • the molar ratio of the compound 1 to the organic base is preferably 1:2-4, more preferably 1:2.5-3.
  • the soluble compound 1 solvent preferably includes dichloromethane, chloroform, toluene or tetrahydrofuran; the present invention has no special limitation on the amount of the soluble compound 1 solvent, as long as it can dissolve compound 1; in this invention
  • the ratio of the amount of compound 1 to the volume of the partially soluble 3-fluoro-4-nitrobenzoic acid solvent is preferably 0.14mol:250mL.
  • the mixing of compound 1, (S)-piperidine-3-ethyl carboxylate, an organic base and a soluble compound 1 solvent is preferably dissolving compound 1 in a partially soluble compound 1 solvent to obtain compound 1 solution; mixing (S)-ethyl piperidine-3-carboxylate, an organic base and the remaining soluble compound 1 solvent to obtain a mixed solution; adding the compound 1 solution dropwise to the mixed solvent.
  • the amount of the partially soluble compound 1 solvent there is no special limitation on the amount of the partially soluble compound 1 solvent, as long as the compound 1 can be dissolved;
  • the ratio is preferably 0.14mol: 100mL;
  • the present invention has no special limitation on the amount of solvent for the remaining soluble compound 1, as long as (S)-piperidine-3-ethyl carboxylate can be dissolved; in an embodiment of the present invention,
  • the ratio of the amount of the (S)-ethyl piperidine-3-carboxylate to the volume of the remaining soluble compound 1 solvent is preferably 0.14mol:50mL.
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the temperature of the acylation reaction is preferably 0-40° C., more preferably room temperature; the time of the acylation reaction is preferably 0.1-6 h, more preferably 0.5-1 h.
  • the reaction occurring in the described acylation reaction process is as follows:
  • the present invention preferably further includes solid-liquid separation of the acylation reaction system to obtain a liquid component and a solid component; washing the obtained solid product until colorless, and separating the solid-liquid separation obtained liquid component After separation and washing, the obtained liquid components were combined and then concentrated, extracted with water and extracted with an organic solvent in sequence. After combining the organic phases, they were washed with hydrochloric acid solution, water and saturated saline in sequence, and the obtained organic phase was concentrated to a constant weight to obtain compound 2.
  • the method of concentration is preferably vacuum distillation.
  • the ratio of the amount of ethyl (S)-piperidine-3-carboxylate to the volume of extraction water is preferably 0.14mol:200mL.
  • the organic solvent for organic solvent extraction preferably includes dichloromethane, chloroform, toluene or tetrahydrofuran; the number of extractions with the organic solvent is preferably 2 to 3 times; the (S)-piperidine-3-
  • the ratio of the amount of ethyl formate to the volume of the organic solvent used for single extraction is preferably 0.14mol: 250mL.
  • the concentration of the hydrochloric acid solution is preferably 1 to 6mol/L, and more preferably 1mol/L; The ratio is preferably 0.14mol:270mL.
  • the ratio of the amount of (S)-piperidine-3-ethyl carboxylate to the volume of washing water is preferably 0.14mol:200mL. In the present invention, the ratio of the amount of (S)-piperidine-3-ethyl carboxylate to the volume of saturated saline is preferably 0.14mol:200mL.
  • the present invention mixes the compound 2, a metal reducing agent, an acidic reagent and a soluble compound 2 solvent to perform a reduction reaction to obtain compound 3 ((S)-1-(4-3-fluoroaminobenzidine acyl)piperidine-3-carboxylic acid ethyl ester).
  • the metal reducing agent preferably includes iron and/or zinc;
  • the acidic reagent preferably includes one or more of ammonium chloride, acetic acid and hydrochloric acid;
  • the hydrochloric acid is preferably used in the form of hydrochloric acid solution;
  • the concentration of the hydrochloric acid solution is preferably 0.1-6, more preferably 0.5-1.
  • the molar ratio of the compound 2, the metal reducing agent and the acidic reagent is 1:3.3-5:5-20, more preferably 1:4-4.5:10-15.
  • the solvent of the soluble compound 2 is preferably an aqueous alcohol solution; the alcohol in the aqueous alcohol solution preferably includes methanol and/or ethanol, and the volume ratio of alcohol to water in the aqueous alcohol solution is preferably 1:0.3-2, More preferably, it is 1:0.8-1.2.
  • the present invention has no special limitation on the amount of the partially soluble compound 1 solvent, as long as it can dissolve compound 2; in the embodiments of the present invention, the ratio of the amount of the compound 2 to the volume of the soluble compound 2 solvent Preferably it is 0.14mol:400mL.
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the temperature of the reduction reaction is preferably 50-100° C., more preferably 60-80° C.; the reduction reaction time is preferably 0.1-6 h, more preferably 0.25-1 h.
  • the reaction occurring in the reduction reaction process is as follows:
  • the present invention preferably also includes cooling the system of the reduction reaction to room temperature and suctioning diatomaceous earth to obtain a suction filtrate and a filter cake, and washing the filter cake with alcohol to obtain an alcohol washing solution;
  • the suction filtrate and alcohol washing liquid are combined and concentrated under reduced pressure to remove alcohol;
  • the obtained concentrate is sequentially subjected to organic solvent extraction, water washing, saturated saline washing, desiccant drying, suction filtration to remove desiccant, vacuum concentration and silica gel column layer Purified by analysis to obtain compound 3.
  • the particle size of the diatomite used for suction filtration of the diatomite is preferably 200-300 mesh.
  • the alcohol used for alcohol washing preferably includes ethanol, methanol or isopropanol; the method of alcohol washing is preferably alcohol rinsing; the ratio of the amount of substance of the compound 2 to the volume of alcohol is preferably 0.14 mol: 50mL.
  • the organic solvent for extraction preferably includes ethyl acetate, dichloromethane, methyl isobutyl ketone or n-butanol; the number of extractions with the organic solvent is preferably 2 to 3 times; the compound 2 The ratio of the amount of substance to the volume of the organic solvent is preferably 0.14 mol:200 mL.
  • the ratio of the amount of compound 2 to the volume of washing water is preferably 0.14mol:200mL.
  • the ratio of the amount of compound 2 to the volume of saturated saline is preferably 0.14mol:200mL.
  • the desiccant preferably includes anhydrous sodium sulfate or anhydrous magnesium sulfate.
  • the mass ratio of the crude product to the silica gel for loading is preferably 1:1 to 3, more preferably 1:1.5, and the silica gel packed in the crude product and the silica gel column
  • the mass ratio is preferably 1:2 ⁇ 10, more preferably 1:5
  • the eluent used in the silica gel column chromatography purification is preferably ethyl acetate (EA) and petroleum ether (PE),
  • the volume ratio of ethyl acetate to petroleum ether is preferably 1:1-20, more preferably 1:5.
  • the present invention mixes compound 3, solid phosgene, an organic base and a soluble compound 3 solvent to perform a nucleophilic substitution-elimination reaction to obtain an isocyanate intermediate solution.
  • the organic base preferably includes one or more of triethylamine, N,N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine.
  • the molar ratio of compound 3, solid phosgene, organic base and memantine is 1:0.34 ⁇ 1:4 ⁇ 10:1 ⁇ 1.5, more preferably 1:0.5 ⁇ 0.8:5 ⁇ 8:1.2 ⁇ 1.3.
  • the soluble compound 3 solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile, toluene or tetrahydrofuran; the soluble compound 3 solvent is preferably a dry solvent; the present invention is for the soluble compound 3 solvent
  • the amount of compound 3 used is not particularly limited, as long as the compound 3 can be dissolved; in the embodiment of the present invention, the ratio of the compound 3 substance amount to the soluble compound 3 solvent volume is preferably 0.076mol:800mL.
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the order of mixing is preferably dissolving the solid phosgene in the first part of the soluble compound 3 solvent to obtain a solid phosgene solution; dissolving the organic base in the second part of the soluble compound 3 solvent to obtain the organic Alkaline solution: Dissolve compound 3 in the remaining soluble compound 3 solvent, cool down in an ice-salt bath to below 0°C, add solid phosgene solution, and then add organic alkali solution dropwise.
  • the ratio of the amount of the substance of the solid phosgene to the volume of the first part of the soluble compound 3 solvent is preferably 0.038mol: 100mL; the amount of the substance of the organic base and the volume of the second part of the soluble compound 3 solvent The ratio is preferably 0.46mol: 100mL; the ratio of the amount of the compound 3 substance to the volume of the remaining soluble compound 3 solvent is preferably 0.076mol: 600mL.
  • the temperature after the cooling is preferably -20 to 0°C; the present invention has no special restrictions on the salt in the ice-salt bath, as long as the temperature of the ice-salt bath can reach -20°C, specifically, chlorine sodium chloride.
  • the temperature of the nucleophilic substitution-elimination reaction is preferably -10 to 30°C, more preferably -5 to 0°C; the nucleophilic substitution-elimination time is preferably 0.5 to 4h, more preferably 1 ⁇ 3h.
  • the present invention mixes the isocyanate intermediate solution, memantine and a soluble memantine solvent, and then performs a nucleophilic substitution reaction to obtain compound 4.
  • the soluble memantine solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile, toluene or tetrahydrofuran; the ratio of the amount of the memantine substance to the volume of the soluble memantine solvent is preferably 0.076mol: 100mL.
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the temperature of the nucleophilic substitution reaction is preferably -10 to 30°C, more preferably -5 to 0°C; the time of the nucleophilic substitution reaction is preferably 0.5 to 4h, more preferably 1 to 3h .
  • the reactions occurring in the described nucleophilic substitution-elimination reaction and nucleophilic substitution reaction process are as follows:
  • the present invention concentrates the nucleophilic substitution reaction system to constant weight to obtain compound 4.
  • the method of concentration is preferably vacuum distillation.
  • the present invention hydrolyzes said compound 4 to obtain compound II ((S)-1-(4- ⁇ 3-[(1r,3R,5S,7S)-3,5-dimethyladamantine alk-1-yl]ureido ⁇ -3-fluorobenzoyl)piperidine-3-carboxylic acid).
  • the hydrolysis is preferably carried out in the presence of an inorganic base, and the inorganic base preferably includes hydroxide and/or carbonate; the hydroxide preferably includes lithium hydroxide, sodium hydroxide and hydroxide One or more of potassium; the carbonate preferably includes potassium carbonate and/or sodium carbonate.
  • the molar ratio of the compound 4 to the inorganic base is preferably 1:3-20, more preferably 1:5-10.
  • the solvent for the hydrolysis preferably includes a mixed solvent of organic solvent/water;
  • the organic solvent in the mixed solvent preferably includes methanol, ethanol, tetrahydrofuran, acetone or acetonitrile;
  • the organic solvent and water in the mixed solvent The volume ratio is preferably 1:0.2-5, more preferably 1:1-3; the present invention has no special limitation on the amount of the hydrolysis solvent, as long as it can dissolve compound 4; in the embodiments of the present invention, the The ratio of the amount of compound 4 to the volume of the solvent for hydrolysis is preferably 0.079mol: 400mL.
  • the temperature of the hydrolysis reaction is preferably 5-100° C., more preferably 20-50° C.; the time of the hydrolysis reaction is preferably 0.5-5 hours, more preferably 1-2 hours.
  • the reaction that takes place is as follows:
  • the present invention preferably includes concentrating the system of the hydrolysis reaction, adding water to the obtained concentrate, cooling the temperature in an ice-salt bath to below 0°C, separating the solid from the liquid after acidification, washing the obtained solid product with water, and then drying , to obtain compound II.
  • the ratio of the amount of compound 4 to the volume of added water is preferably 0.079mol:500mL.
  • the temperature after the cooling is preferably -20 to 0°C; the present invention has no special restrictions on the salt in the ice-salt bath, as long as the temperature of the ice-salt bath can reach -20°C, specifically, chlorine sodium chloride.
  • the inorganic acid used in the acidification preferably includes hydrochloric acid, sulfuric acid or phosphoric acid; the acid is preferably used in the form of an acid solvent; the concentration of the acid solution is preferably 0.5 to 12 mol/L, more preferably 6 mol/L ; The pH value after the acidification is preferably 1-6, more preferably 3.
  • the method of solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art can be used, such as suction filtration.
  • the water washing is preferably water rinsing; the ratio of the amount of compound 4 to the volume of washing water is preferably 0.079mol:100mL.
  • the drying temperature is preferably 10-40° C., more preferably 20-30° C.; the drying time is preferably 1-12 hours, more preferably 4-8 hours.
  • the present invention mixes the compound II, a chlorination reagent, a catalyst and a soluble compound II solvent, and then performs a chlorination reaction to obtain an acid chloride intermediate.
  • the chlorination reagent preferably includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
  • the catalyst preferably includes a Lewis acid and/or a Lewis base;
  • the Lewis acid preferably includes one of zinc chloride, aluminum trichloride, boron trifluoride, iron trichloride and tin chloride or several;
  • the Lewis base preferably includes one or more of N,N-dimethylformamide (DMF), pyridine and 4-dimethylaminopyridine.
  • the molar ratio of the compound II, the chlorination reagent and the catalyst is preferably 1:1.05-2:0.001-0.01, more preferably 1:1.2-1.5:0.005-0.008.
  • the solvent for the soluble compound II preferably includes chlorinated hydrocarbon solvents, heterocyclic solvents or nitrile solvents; the chlorinated hydrocarbon solvents preferably include dichloromethane or chloroform; the heterocyclic
  • the class solvent preferably includes tetrahydrofuran or dioxane; the nitrile solvent preferably includes acetonitrile; the soluble compound II solvent is preferably a dry solvent; the present invention has no special limitation on the amount of the soluble compound II solvent, and can be Compound II can be dissolved; in the embodiment of the present invention, the amount of the substance of the compound II and 0.075mol of the soluble compound II solvent: 280mL.
  • the order of mixing is preferably to mix compound II, catalyst and partially soluble compound II solvent to obtain a mixed solution; to mix the chlorination reagent and the remaining soluble compound II solvent to obtain a compound II solution;
  • the compound II solution is added dropwise into the mixed solution;
  • the present invention has no special limitation on the amount of the partially soluble compound II solvent, as long as the compound II can be dissolved; in the embodiments of the present invention, the compound II
  • the ratio of the amount of the substance and the volume of the partially soluble compound II solvent is preferably 0.075mol: 250mL; the present invention has no special limitation on the amount of the remaining soluble compound II solvent, as long as the chlorinated reagent can be dissolved; in the present invention
  • the ratio of the amount of the chlorinated reagent to the volume of the remaining soluble compound II solvent is preferably 0.094mol:50mL.
  • the mixing method is preferably stirring and mixing, and the speed and time of the stirring and mixing are not particularly limited in the present invention, as long as the raw materials can be mixed evenly.
  • the temperature of the chlorination reaction is preferably 0-80°C, more preferably room temperature; the time of the chlorination reaction is preferably 0.1-6h, more preferably 1-2h; the chlorination reaction process , compound II reacts with a chlorination reagent to generate an acid chloride intermediate.
  • the present invention preferably further includes concentrating the chlorination reaction system to a constant weight to obtain an acid chloride intermediate; the method of concentrating is preferably vacuum distillation.
  • the present invention mixes the acid chloride intermediate, ammonia solution, ice and a soluble acid chloride intermediate solvent, and performs an acylation reaction to obtain the sEH inhibitor having the structure shown in formula I.
  • the solvent in the ammonia solution preferably includes water, alcohol solvents, ether solvents, chlorinated hydrocarbon solvents, ester solvents, heterocyclic solvents, nitrile solvents or ketone solvents; the alcohols
  • the solvent preferably includes methanol or ethanol; the ether solvent preferably includes ether; the chlorinated hydrocarbon solvent preferably includes methylene chloride or chloroform; the ester solvent preferably includes ethyl acetate; the heterocyclic solvent preferably includes Tetrahydrofuran or dioxane; the nitrile solvent preferably includes acetonitrile; the ketone solvent preferably includes acetone; the mass concentration of the ammonia solution is preferably 5-28%, more preferably 10-20%.
  • the molar ratio of the compound II to ammonia in the ammonia solution is preferably 1:5-20, more preferably 1:10-15.
  • the soluble acid chloride intermediate solvent preferably includes a chlorinated hydrocarbon solvent or a heterocyclic solvent; the chlorinated hydrocarbon solvent preferably includes methylene chloride or chloroform; the heterocyclic solvent preferably includes tetrahydrofuran or dioxane; the soluble acid chloride intermediate solvent is preferably a dry solvent; the present invention has no special limitation on the amount of the acid chloride intermediate solvent, as long as the acid chloride intermediate can be dissolved; in the embodiments of the present invention, The ratio of the substance amount of the acid chloride intermediate to the volume of the soluble acid chloride intermediate solvent is preferably 0.075mol:200mL.
  • the mixing method is preferably stirring and mixing, and the present invention has no special limitation on the speed and time of the stirring and mixing, as long as the raw materials can be mixed evenly;
  • the order of mixing is preferably the acid chloride intermediate solvent In the soluble acid chloride intermediate solvent, the acid chloride intermediate solution is obtained; the ammonia solution and ice are cooled to 0°C in an ice bath, and then the acid chloride intermediate solution is added dropwise;
  • the present invention has no special limitation on the dropping speed , added dropwise at a uniform speed.
  • the temperature of the acylation reaction is preferably -10 to 0°C, more preferably -5 to -2°C; the time of the acylation reaction is preferably 2 to 10 hours, more preferably 5 to 8 hours.
  • the reaction that takes place in described chlorination reaction and acylation reaction process is as follows:
  • the present invention preferably further comprises layering the system of the acylation reaction, concentrating the obtained organic phase to a constant weight, adding water to the obtained concentrate for stirring, separating solid and liquid, and separating the obtained solid product After drying, the obtained crude product was purified by silica gel column chromatography to obtain the sEH inhibitor having the structure shown in formula I.
  • the method of concentration is preferably vacuum distillation.
  • the ratio of the amount of compound II to the volume of water added is preferably 0.075mol:500mL; the present invention has no special limitations on the stirring speed and time, and it can be uniformly dispersed without splashing the liquid Can.
  • the method of solid-liquid separation is not particularly limited, and a solid-liquid separation method well known to those skilled in the art can be used, such as suction filtration.
  • the drying temperature is preferably 10-40° C., more preferably 20-30° C.; the drying time is preferably 1-12 hours, more preferably 4-8 hours.
  • the mass ratio of the crude product to the silica gel for loading is preferably 1:1 to 3, more preferably 1:1.5, and the silica gel packed in the crude product and the silica gel column
  • the mass ratio is preferably 1:2 ⁇ 10, more preferably 1:5
  • the eluent used in the silica gel column chromatography purification is preferably ethyl acetate (EA) and petroleum ether (PE), the ethyl acetate
  • the volume ratio to petroleum ether is preferably 1:1-20, more preferably 1:5-10.
  • the present invention provides the sEH inhibitor described in the above technical scheme or its pharmaceutically acceptable derivative or composition or the sEH inhibitor or its pharmaceutically acceptable derivative or composition prepared by the preparation method described in the above technical scheme Application in the preparation of medicines for treating sEH-mediated diseases.
  • the present invention provides the sEH inhibitor described in the above technical scheme or its pharmaceutically acceptable derivative or composition or the sEH inhibitor or its pharmaceutically acceptable derivative or composition prepared by the preparation method described in the above technical scheme Use in the treatment of sEH-mediated diseases.
  • the sEH-mediated disease preferably includes pain, inflammation, cardiovascular disease, neurodegenerative disease, metabolic disease or renal disease.
  • the pain includes neuropathic pain, inflammatory pain or cancer pain.
  • the inflammation includes sepsis, neuroinflammation, inflammatory bowel disease, chronic peptic ulcer or arthritis.
  • the cardiovascular disease includes hypertension, cardiomyopathy, stroke or atherosclerosis.
  • the neurodegenerative disease includes Parkinson's syndrome, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis.
  • the metabolic disease includes diabetes or gout.
  • the effective dose of the sEH inhibitor is preferably determined according to different diseases and symptoms of patients, and is specifically preferably 10-500 mg.
  • the administration frequency of the preparation of the sEH inhibitor is preferably determined according to the treatment plan, specifically preferably once a week, once every 5 days, once every 3 days, once every 2 days, once a day, twice a day , three times a day, four times a day, five times a day, hourly or any higher frequency.
  • the administration method of the sEH inhibitor preferably includes oral administration, injection or infusion; intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, sublingual, and intraocular).
  • the dosage form of the sEH inhibitor preferably includes tablet, capsule, oral tincture, oral pill, oral granule, oral powder, oral powder, external tincture, external ointment, external patch, external powder, external application Tablets, suppositories or injections; said tablets preferably include enteric-coated tablets, coated tablets, film-coated tablets, sugar-coated tablets, extract tablets, dispersible tablets, scored tablets, sustained-release tablets, sustained-release coated tablets or controlled-release tablets tablets; the capsules preferably include hard capsules, soft capsules (capsules), enteric-coated capsules, sustained-release capsules or controlled-release capsules; the oral tincture preferably includes oral solutions, oral suspensions, oral emulsions, gelatin Slurry, oral liquid, emulsion, emulsion, colloidal solution, mixture, tincture, drop or suspension drop; said oral pill preferably includes bolus, drop pill or honeyed pill; said oral granule, oral powder and oral powder Independently
  • the volume of ethyl acetate used for a single extraction is 250mL. After combining the organic phases, use 270mL of hydrochloric acid solution with a concentration of 1mol/L washed with 200 mL of water and 200 mL of saturated brine, and the obtained organic phase was concentrated under reduced pressure to constant weight to obtain compound 2 (brownish red oil, 50.2 g).
  • the obtained crude product is purified by silica gel column chromatography.
  • the mass ratio of the crude product and the silica gel used for loading the sample is 1:1.5, and the mass ratio of the crude product and the silica gel packed in the silica gel column is 1:5;
  • the eluent used in the silica gel column chromatography purification is preferably EA and PE, and the volume ratio of EA and PE is 1:5 to obtain compound 3 (26.05g, the total yield of step (1) and step (2) is 65.6g %).
  • the time is 2h, after the reaction is completed, the layers are separated, the obtained organic phase is concentrated under reduced pressure to constant weight, 500mL of water is added to the obtained concentrate, stirred, and then suction filtered, the obtained solid product is dried to obtain a crude product, and the obtained crude product is subjected to silica gel Purified by column chromatography to obtain the sEH inhibitor having the structure shown in formula I (20 g, the purity is 98%, the total yield of steps (1) to (5) is 31%, and the sEH inhibitor is denoted as GL-B437); wherein , in the purification process of silica gel column chromatography, the mass ratio of crude product and loading silica gel is 1:1.5, the mass ratio of crude product and the silica gel packed in the silica gel column is 1:5, and the volume ratio of eluent is 1: 1 mixed solvent of EA and PE.
  • the purity of compound GL-B437 was determined by Shimadzu 2010A HPLC, and the purity was 98% (area normalization method).
  • the concentration of human liver microsomes is 0.5mg/mL, and the concentration of SD rat liver microsomes is 0.53mg/mL.
  • the half-life of GL-B437 in human liver microsomes is 174min, and the half-life in rat liver microsomes is 120min.
  • the volume of ethyl acetate was 20mL, and the pH value of the aqueous layer was adjusted to 2 with 1M hydrochloric acid, and then extracted three times with ethyl acetate, and the volume of ethyl acetate was 20mL for a single extraction. Once, dried over anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to constant weight to obtain P2 (0.7 g, light yellow liquid, yield 52.0%).
  • sEH can hydrolyze the epoxy ring in the PHOME substrate, and release cyanohydrin through intramolecular cyclization.
  • cyanohydrins are rapidly decomposed into cyanide ions and 6-methoxy-2-naphthaldehyde, the latter has a strong fluorescence signal at an excitation wavelength of 330nm and an emission wavelength of 465nm, which is similar to that of sEH Inhibition is inversely proportional to strength.
  • the inhibition rates of samples with different concentrations were calculated. According to the inhibitory rate and concentration, the IC 50 of the compound was used with IBM SPSS statistics 20 software.
  • PHOME substrate solution Dissolve PHOME in DMSO to obtain a PHOME solution with a concentration of 20mM, and store it in a -80°C refrigerator; prepare it for immediate use, and dilute it with Tris-HCl buffer to a concentration of 1/3mM.
  • sEH solution Take 1 ⁇ L of 5 mg/mL sEH and add 499 ⁇ L Tris-HCl buffer solution to make a 10 ⁇ g/mL mother solution, and store in a -80°C refrigerator. When used, it was diluted with Tris-HCl buffer to a concentration of 4 ⁇ g/mL.
  • the GL-B437 compound was dissolved in DMSO into a 20mM solution, and stored in a -20°C refrigerator for later use; before use, the 20mM high-concentration compound was diluted with DMSO to a total of five concentrations: 100nM, 50nM, 25nM, 12.5nM, 6.25nM.
  • the fluorescence signal data is detected by a microplate reader, the excitation wavelength is 330nm, and the emission wavelength is 465nm.
  • the IC 50 of the compound was calculated using IBM SPSS statistics 20 software according to the inhibition rate and concentration.
  • ⁇ M is ⁇ mol/L.
  • Test results The IC 50 of GL-B437 against recombinant human sEH is 0.06nM.
  • Multi-tube vortex oscillator DMT-2500, Hangzhou Miou Instrument Co., Ltd.
  • Liquid phase Vanquish UPLC, Thermo Fisher.
  • Triple quadrupole LC-MS TSQAltis, Thermo Fisher.
  • Vehicle for intravenous injection 8% absolute ethanol + 4% Tween 80 + 88% normal saline (volume fraction).
  • Drug preparation preparation method Weigh the sample in the container, pipette 8% absolute ethanol to fully dissolve the sample, add 4% Tween 80, stir until clear and transparent, add 88% normal saline, and fully stir until a clear and transparent solution .
  • Oral administration vehicle 0.5% CMC-Na suspension.
  • Preparation method of the drug preparation accurately weigh the corresponding drug and place it in an EP tube, add a quantitative 0.5% CMC-Na aqueous solution, and make a suspension through ultrasonic crushing, store it at 4°C after stabilization, and vortex before use .
  • the dose of intravenous injection of SD rats in GL-B437 group was 10 mg/kg; the dose of intragastric administration group was 50 mg/kg.
  • Sample analysis Take 50 ⁇ L of the sample to be tested, add 50 ⁇ L of internal standard working solution (tadalafil 20.000 ng/mL), vortex and mix, add 300 ⁇ L of acetonitrile, vortex and mix for 10 min, centrifuge at 4 °C and 4200 rpm for 10 min , add 150 ⁇ L of supernatant to 150 ⁇ L of pure water, vortex and mix well, centrifuge at 4°C and 4200 rpm for 10 min, and take supernatant for injection.
  • internal standard working solution tadalafil 20.000 ng/mL
  • Div represents the dose administered by intravenous injection
  • Dpo represents the dose administered by oral administration
  • AUCiv represents the area under the drug-time curve for intravenous administration
  • AUCpo represents the area under the curve for oral administration.
  • the peak time was 38min
  • the total exposure under the drug-time curve AUC 0-24h was 2620.520ng h/L
  • the half-life was 5.179h
  • the absolute bioavailability of GL-B437 was 28.6 %.
  • Fig. 1 is the drug-time curve after tail vein injection and gavage administration, as can be seen from Fig. 1, compound GL-B437 reaches peak concentration in rat body after intravenous injection administration 5min, and blood drug concentration decreases gradually with time; The concentration of compound GL-B437 reached the peak in rats 38 minutes after gastric administration, and the plasma concentration gradually decreased with time.
  • mice Male ICR mice, 3. The animals were raised in Room 612 (mouse room) of the new scientific research building of Shenyang Pharmaceutical University, the ambient temperature was kept at 20°C-24°C, the humidity was about 50%, and they had free access to food and water.
  • Suspension preparation of compound GL-B437 with the maximum intragastric concentration Weigh 0.7498 g of compound GL-B437, add it to 2.5 ml of 0.5 wt% CMC-Na solution, and ultrasonically crush it to prepare a suspension.
  • Micro vortex mixer Shanghai Jingke Industrial Co., Ltd., H-1;
  • mice were divided into two groups, one in the blank control group and two in the compound B437 group.
  • the compound B437 group was intragastrically administered 6.0 g/kg, and the administration volume was 20 ml/kg, and the blank control group was intragastrically administered the same amount of distilled water.
  • mice Male, were randomly divided into compound B437 group and blank group. Give the maximum volume (20ml/kg) that can be fed respectively, the compound GL-B437 suspension (0.3g/ml) that can be fed with the maximum concentration, the dosage is 6.0g/kg, and the blank group is fed with the same volume Distilled water (20ml/kg).
  • the changes in the mice's autonomous activities, eating, excretion, eyes and nose, etc. were recorded, and the observation was continued for 14 days, and the body weight of the mice was recorded every day.
  • mice were given 6.0g/kg of compound GL-B437 orally and observed continuously for 14 days, and there was no animal death or abnormal reaction visible to the naked eye. It shows that GL-B437 did not show any toxicity and adverse reactions after oral administration of 6g/kg in mice.
  • Figure 2 is the result of comparing the body weight of the mice in the control group and the administration group. It can be seen from Figure 2 that the body weight monitoring for 14 consecutive days shows that compared with the control group, the compound GL-B437 has no effect on the body weight of the mice.
  • Test compound GL-B437, and positive controls are gabapentin and EC-5026.
  • SC-15 digital display constant temperature water bath Ningbo Xinzhi Biotechnology Co., Ltd.
  • VORTEX-5 vortex mixer Haimen Qilinbeier Instrument Manufacturing Co., Ltd.
  • the rats were randomly divided into groups according to body weight, and divided into control group, model group, gabapentin group, GL-B437 group (four doses), EC-5026 group and sham operation group, and the sham operation group was used as a negative control group. It is to verify whether the model is established successfully, and does not need to participate in statistics. During the experiment, the amount of experimental data in each group is n ⁇ 6. After the induced pain occurs (3 to 5 days after modeling), the drug is administered regularly once a day and administered continuously.
  • Drug preparation Accurately weigh the corresponding drug and place it in a 15mLEP tube, add quantitative 0.5% carboxymethylcellulose sodium aqueous solution, and make a suspension through ultrasonic crushing, and store it at 4°C after stabilization.
  • the way of administration is oral, and the dosage is 1 mg/kg/d, 3 mg/kg/d, 9 mg/kg/d, 27 mg/kg/d, once every 12 hours, for 20 consecutive days. Dosage and grouping are shown in Table 3:
  • Spontaneous painful behaviors will appear after modeling: (1) Scratching: Raise the rear left or right paw to quickly move the claws and claws to grab various parts of the body; (2) Bite: Pierce the left side of the body with the mouth and teeth. side or right skin.
  • Figure 3 is the comparison result of the paw contraction threshold, wherein a is the comparison result of the paw contraction threshold between the control group and each treatment group, and b is the comparison result of the paw contraction threshold between the control group and each treatment group before administration. It can be seen from a in Figure 3 that compared with the control group and the sham operation group, the paw retraction threshold of the rats in the model group was significantly lower, with a significant difference, indicating that the SNI model was successfully prepared. It can be seen from b in Figure 3 that compared with the control group, the PWT of the sham operation group decreased slightly, but there was no statistical significance.
  • the PWT of the model group decreased significantly, and the difference was statistically significant ( *** P ⁇ 0.001); compared with the sham operation group, the PWT decreased significantly, and the difference was statistically significant ( ### P ⁇ 0.001).
  • the PWT value of each administration group before administration the paw retraction threshold of each administration group before the first administration was significantly lower, and the difference in PWT among each group was statistically significant ( *** P ⁇ 0.001), which was significant
  • Figure 4 is the comparison result of the paw contraction threshold between the model group and each administration group. It can be seen from Figure 4 that the relief of SNI neuropathic pain in SD rats is manifested as a significant increase in PWT.
  • PWT On the first day of administration, 3 mg/kg of GL-B437 /d, 9mg/kg/d, 27mg/kg/d administration group PWT was significantly higher than the model group, with statistical difference ( * P ⁇ 0.05, ** P ⁇ 0.01); the second day of continuous administration , 27mg/kg/d of GL-B437, PWT of GP group was significantly higher than that of model group, with statistical difference ( # P ⁇ 0.05); on the 4th day of continuous administration, 9mg/kg/d of GL-B437 , 27mg/kg/d, gabapentin, EC-5026 administration group PWT was significantly higher than the model group, with statistical difference ( $ P ⁇ 0.05, $$ P ⁇ 0.01); on the 8th day of continuous administration
  • Gabapentin is the ligand of the ⁇ 2 ⁇ subunit of the voltage-dependent calcium channel, which can reduce the influx of calcium ions, thereby reducing the release of excitatory transmitters and spinal cord sensitization, and has a good therapeutic effect on neuropathic pain. Due to the limited number of ligands in animals, continuous administration is easy to saturate, and it is easy to cause tolerance, which in turn leads to a decrease in drug efficacy. After 20 days of continuous administration, the analgesic effect of gabapentin was significantly reduced, which was significantly weaker than that of the 3 mg/kg/d and 9 mg/kg/d administration groups of the GL-B437 group.
  • the analgesic test showed that GL-B437 had significant analgesic effect on neuropathic pain caused by SNI, and the low dose group showed obvious dose dependence, among which the doses of 3mg/kg/d and 9mg/kg/d had analgesic effect Optimum, the analgesic effect is better than gabapentin and EC-5026, and the analgesic effect of the 1mg/kg/d administration group is weaker.
  • Figure 5 is the drug time-effect curve after the last administration.
  • the rats in the 3mg/kg/d and 9mg/kg/d administration groups of GL-B437 were at the same time after administration. It exhibited obvious analgesic effect within 2 hours and lasted for more than 6 hours. Both the onset speed and the analgesic effect were superior to gabapentin and EC-5026.

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Abstract

La présente invention concerne un inhibiteur de sEH ou une composition pharmaceutiquement acceptable de celui-ci, un procédé de préparation correspondant et une utilisation associée, se rapportant au domaine technique de la médecine. L'inhibiteur de sEH selon la présente invention a une structure telle que représentée par la formule I. L'inhibiteur de sEH fourni par la présente invention peut stabiliser un acide gras époxy de substance endogène ayant une large gamme d'activités physiologiques, a un effet inhibiteur très puissant sur la sEH recombinante humaine, et peut évidemment soulager la douleur neuropathique au moyen de divers mécanismes d'action de régulation de la génération de diverses cytokines pro-inflammatoires, réduire le stress du réticulum endoplasmique, prévenir ou inverser le dysfonctionnement endothélial et la stabilisation des fonctions mitochondriales, et peut également éviter efficacement des réactions indésirables associées à une cible. De plus, la structure inhibitrice de sEH fournie par la présente invention ne contient pas de carboxyle libre, peut empêcher des réactions indésirables, telles que l'irritation gastro-intestinale provoquée par l'administration orale, et présente une faible réaction défavorable, une biodisponibilité élevée, un excellent effet analgésique et la quantité de dosage de celle-ci est faible.
PCT/CN2022/073959 2021-06-22 2022-01-26 Inhibiteur de seh ou composition pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée Ceased WO2022267470A1 (fr)

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WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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CN113402447B (zh) * 2021-06-22 2022-10-18 沈阳药科大学 一种sEH抑制剂或其药学上可接受的组合物及其制备方法和应用
CN115819328B (zh) * 2022-11-18 2024-08-27 沈阳药科大学 美金刚脲类衍生物及其制备方法和在制备治疗可溶性环氧化物酶介导的疾病的药物中的应用
CN118206542B (zh) * 2023-03-22 2025-06-27 沈阳药科大学 一种化合物及其制备方法和在制备sEH抑制剂与PPARs激动剂中的应用

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* Cited by examiner, † Cited by third party
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WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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