WO2020237749A1 - Long-acting compound - Google Patents

Long-acting compound Download PDF

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WO2020237749A1
WO2020237749A1 PCT/CN2019/091697 CN2019091697W WO2020237749A1 WO 2020237749 A1 WO2020237749 A1 WO 2020237749A1 CN 2019091697 W CN2019091697 W CN 2019091697W WO 2020237749 A1 WO2020237749 A1 WO 2020237749A1
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acyl
independently selected
compound
aryl
salts
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PCT/CN2019/091697
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French (fr)
Chinese (zh)
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周强
叶涛
李书鹏
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北京大学深圳研究生院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This application relates to the field of medicine, and specifically to a compound for treating depression, neuropathic and chronic pain, including complex regional pain syndrome (CRPS).
  • CRPS complex regional pain syndrome
  • Ketamine is a representative of intravenous anesthetics of phencyclidine commonly used in clinical practice, and it is one of the rapid development of clinical and basic research in recent years. In clinical practice, it is often used to meet the anesthesia needs of pediatrics, obstetrics, perioperative patients and patients with special diseases because of its characteristics such as rapid induction, shorter action time, faster awakening, and less impact on the respiratory and circulatory systems.
  • Ketamine was first synthesized in 1962, used in humans in 1965, and was officially approved by the FDA for clinical use in 1970. Its typical "separation anesthesia" and short-acting precise analgesia made it a smash hit, but then it was discovered that mental side effects and the rapid development of other intravenous anesthetics have greatly reduced the clinical use of ketamine. In the past 10 years, with the research on the usage and dosage of ketamine, and its anti-inflammatory, antidepressant, neuroprotective, analgesic and other effects have been discovered, the medical community has renewed interest in ketamine.
  • Ketamine has both neurotoxic and neuroprotective effects.
  • the huge surgical stimulation may theoretically balance the damage of anesthesia, while ketamine can reduce the neurocognitive damage caused by surgical injury stimulation. Does ketamine cause neuroprotection or nerve damage and the dosage of ketamine? There is a direct correlation.
  • Ketamine has an effect on postoperative cognitive function.
  • numerous clinical trials have confirmed that a single small dose of ketamine during surgery can reduce the incidence of postoperative cognitive dysfunction (POCD).
  • POCD postoperative cognitive dysfunction
  • Ketamine has an analgesic effect.
  • Sub-anaesthetic doses of ketamine are often used for the treatment of hyperalgesia and acute and chronic pain.
  • gargle with ketamine salt water mixture before induction of anesthesia can significantly reduce the incidence and severity of postoperative sore throat caused by general anesthesia tracheal intubation.
  • the use of opioids during surgery increases the amount of opioid analgesia after surgery. This effect is called opioid tolerance.
  • opioid tolerance It has been clinically found that the use of ketamine can prevent opioid tolerance and can also reverse morphine tolerance and enhance the analgesic effect of morphine.
  • Studies have also confirmed that the intraoperative application of low-dose ketamine can prevent remifentanil-induced postoperative hyperalgesia.
  • ketamine can significantly improve the satisfaction of postoperative analgesia, and the sedation score is lower than that of the ketamine combined midazolam group.
  • Ketamine has lung protection.
  • ketamine has been found to have significant lung protection.
  • Clinical experiments have confirmed that both intravenous and aerosolization before one-lung ventilation in thoracic surgery can reduce the level of inflammatory factors in the blood, and aerosol inhalation is more beneficial to the cardiovascular system and airway pressure, while the effect of aerosolization on the side of lung ventilation Better than double lung nebulization.
  • Ketamine is also commonly used clinically in the rescue of fatal asthma attacks when conventional treatment is ineffective, and it is recognized that its use can improve the prognosis.
  • Ketamine has an antidepressant effect.
  • Berman et al. reported for the first time that a single intravenous injection of sub-anaesthetic dose of ketamine (0.5 mg/kg, over 40 minutes intravenously) within 72 hours of more than 50% of patients with Hamilton Depression Scale score reduced by more than 50% (see: Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients [J]. Biol Psychiatry, 2000, 47(4): 351-354).
  • PaulR et al. found that compared with racemic ketamine, S-ketamine has similar antidepressant effects, but has fewer mental side effects (see: Paul R, Schaaff N, Padberg F, et al.
  • This application relates to a compound with antidepressant, anesthesia, analgesic, cognitive function improvement, lung protection, prevention or treatment of amyotrophic lateral sclerosis, or prevention or treatment of complex regional pain syndrome.
  • the compound of the present application has a longer drug effect time, which is specifically manifested in that HNK is metabolized within one week and loses efficacy, while the drug effect time of the compound of the present application can last for more than one week.
  • n is an integer of 0-4;
  • R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
  • R 2 is independently selected from
  • R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
  • R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
  • R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
  • R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
  • n is an integer of 0-4;
  • R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
  • R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
  • R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
  • R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
  • R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
  • the pain includes: chronic pain or neuropathic pain; depression includes: bipolar depression, major depression, depression with neurodegenerative diseases; improvement of cognitive function includes prevention or treatment of Alzheimer’s dementia, Pa Jin Sen et al.
  • n is an integer of 0-4;
  • R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
  • R 5 and R 6 are protecting groups
  • R5 and R6 are H or a protecting group
  • the stereoisomers of all the above compounds include enantiomers and diastereomers.
  • the present invention is not limited to any specific tautomer, but includes all tautomeric forms.
  • isotopes include those atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 11 C, 13 C, and 14 C.
  • the application also provides a pharmaceutical composition.
  • the compound disclosed herein can be administered as a pure chemical, but is preferably administered as a pharmaceutical composition. Therefore, the present disclosure provides a pharmaceutical composition including a compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may include a compound or salt as the sole active agent, but preferably includes at least one other active agent.
  • the pharmaceutical composition contains about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of the compound of formula I and optionally about 0.1 mg to about 2000 mg in a unit dosage form , About 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of other active agents.
  • the compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by oral cavity, rectal, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers Come and give.
  • the pharmaceutical composition can be formulated into any medicinal form, such as aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or ophthalmic solution.
  • Some dosage forms such as tablets and capsules can be subdivided into appropriate dosage unit dosage forms containing appropriate amounts of active ingredients such as effective amounts for the desired purpose.
  • Carriers include excipients and diluents, and must have sufficiently high purity and very low toxicity to make them suitable for administration to the patient to be treated.
  • the carrier may be inert or it may have medicinal benefits by itself.
  • the types of carriers include, but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting Agent, and wetting agent.
  • Some carriers can be listed in more than one category.
  • vegetable oils can be used as lubricants in some formulations and as diluents in others.
  • Exemplary pharmaceutical carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • An optional active agent may be included in the pharmaceutical composition, which does not substantially affect the biological function of the compound of the present invention.
  • the compound or salt of the application may be the only active agent administered or may be administered in conjunction with other active agents.
  • the compound of the application can be administered together with another active agent selected from any of the following:
  • Antidepressants edipram oxalate, felocktine, paroxetine, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, rice Zapine, venlafaxine, atomoxetine, bupropion, doxepine, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, chlorazide Ping, kesepin, olanzapine, quetiapine, risperidone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, donepezil, galantamine, memantine, Rivastigmine, tramiprosate, or their pharmaceutically active salts or prodrugs, or a combination of the above;
  • Schizophrenia drugs aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, triflurazine, olanzapine, crexepin, Flupentixol (flupentioxol), perphenazine, haloperidol, chlorpromazine, fluphenazine, fluphenazine, paliperidone;
  • Alzheimer's dementia drugs donepezil, rivastigmine, galantamine, memantine;
  • Pain drugs acetaminophen, aspirin, NSAIDS, including: diclofenac, difluorobenzenesalicylic acid, etodolac, fenoprofen, flurbiprofen, ibuprofen, indoxine, ketoprofen , Ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, Tolmetinopiods, Cox -2 inhibitors such as celecoxib, and anesthetic pain drugs such as: buprenorphine, butorphanol, codeine, dihydrocodeinone, hydromorphone, hydroxymethyllevormorphan, pethidine , Methadone, morphine, nalbuphine, oxycodone, oxymorphone, analgesic new, propoxyphene, central anal
  • active agents are exemplary rather than comprehensive.
  • Other active agents not included in the above list can be administered in combination with the compound of formula I.
  • the other active agent will be administered at a dose less than generally prescribed and in some cases less than the minimum approved dose, the other active agent may be administered according to its approved prescribed information.
  • the present disclosure includes methods for treating depression, especially bipolar depression and major depression, especially methods for treating treatment-resistant depression, wherein the effective amount of the compound is the lowest that is effective in alleviating the symptoms of depression Dose, where the relief of depressive symptoms is achieved by achieving a 50% or more reduction in the Depressive Symptom Rating Scale score, or a score less than or equal to 7 on HRSD 17 , or less than or equal to 5 on QID-SR 16 , or Less than or equal to 10 on MADRS.
  • the present disclosure provides an amount effective to reduce pain (or analgesia) symptoms; wherein, the reduction of pain symptoms is to achieve a 50% or more reduction in pain symptoms on a pain rating scale.
  • Steps are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.
  • Diastereoisomers are stereoisomers that have two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics and reactivity. In the presence of a resolving agent or chromatography, a chiral HPLC column can be used to separate a mixture of diastereomers under high-resolution analysis steps such as electrophoresis and crystallization.
  • Enantiomers refer to two stereoisomers of a compound that have no overlapping mirror images of each other.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can appear in a chemical reaction or process when there is no stereoselectivity or stereospecificity.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups, and has a specified number of carbon atoms, generally 1 to about 12 carbon atoms.
  • the term C 1 -C 6 alkyl as used herein means an alkyl group having 1 to about 6 carbon atoms.
  • a C 0 -C n alkyl group is used in conjunction with another group in this text, take (phenyl) C 0 -C 4 alkyl as an example, the designated group, in this case, the phenyl group is passed through a single co- The valence bond (C 0 ) is directly bonded or connected through an alkyl chain having the specified number of carbon atoms (in this case, 1 to about 4 carbon atoms).
  • alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
  • alkenyl refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which can occur at any stable point along the chain.
  • the alkenyl groups described herein generally have 2 to about 12 carbon atoms.
  • the alkenyl groups are lower alkenyl groups, those alkenyl groups having 2 to about 8 carbon atoms, such as: C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkenyl groups.
  • Examples of alkenyl include vinyl, propenyl, and butenyl.
  • Alkoxy refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
  • heterocyclic ring means a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing 1 to about 4 heteroatoms selected from N, O, and S and the remaining ring atoms are carbon, or It is a 7 to 11 membered saturated ring, partially unsaturated ring, or aromatic heterocyclic ring system and a 10 to 15-membered tricyclic ring system, which contains at least 1 heteroatom selected from the group consisting of N, O and S polycyclic ring systems And each ring in the polycyclic system contains up to about 4 heteroatoms independently selected from N, O, and S.
  • the heterocyclic ring can be attached to a group where it is substituted at any heteroatom and carbon atom and results in a stable structure.
  • the heterocyclic ring described herein may be substituted on a carbon or nitrogen atom as long as the resulting compound is stable.
  • the nitrogen atom in the heterocyclic ring can optionally be quaternized.
  • the total number of heteroatoms in the heterocyclic group is not more than 4 and preferably the total number of S and O atoms in the heterocyclic group is not more than 2, more preferably not more than 1.
  • heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio (benz[b]thiophenyl), isoquinolinyl, quinazolinyl, quinoxalinyl, Thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidine Group, morpholinyl, piperazinyl, piperidin
  • Aryl or heteroaryl means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heteroaryl group is not more than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than one.
  • the nitrogen atom in the heterocyclic ring can optionally be quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups.
  • substitution may include fusion with a 5- to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O, and S, thereby forming, for example, [1,3]dioxin Azolo[4,5-c]pyridyl.
  • heteroaryl groups include, but are not limited to: pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , And 5,6,7,8-tetrahydroisoquinoline.
  • “Depression” includes low mood, decreased interest in activities, slowed or irritable mental activities, changes in appetite, inattention or indecision, excessive guilt or low self-esteem, and in depression, bipolar depression, and other diseases or conditions caused by Suicidal ideation may occur in the case of mood disorders, substance-induced mood disorders and other unexplained mood disorders, and can also be associated with various other mental illnesses (including but not limited to mental disorders, cognitive disorders, eating disorders, anxiety Syndrome and personality disorder) coexist. The progression of the disease (longitudinal course), medical history, type of symptoms, and etiology help to distinguish the various forms of affective diseases from each other.
  • Salts of compounds are derivatives of the disclosed compounds, wherein the parent compound is modified by preparing a non-toxic acid or its base addition salt, and also refers to these compounds and pharmaceutically acceptable solvates of these salts, including hydrates .
  • pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues such as carboxylic acids; etc., and include one or more A combination of the above salts.
  • Pharmaceutical salts include non-toxic salts and quaternary ammonium salts such as parent compounds formed from non-toxic inorganic or organic acids.
  • non-toxic acid salts include those derived from inorganic acids, such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, Cesium salt, etc.; alkaline earth metal salt such as calcium salt, magnesium salt, etc., and a combination including one or more of the above-mentioned salts.
  • inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.
  • other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, Cesium salt, etc.
  • alkaline earth metal salt such as calcium salt, magnesium salt, etc.
  • the organic salt of the compound includes compounds such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, hexanoic acid, maleic acid, hydroxymaleic acid , Phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methane Salts prepared from organic acids such as sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) n -COOH (where n is 0 to 4); organic amine salts, such as:
  • Step 1 Starting from o-trifluoromethyl benzonitrile, compound D 1 is obtained according to the classic ketamine drug synthesis method Calvin Stevens method (shown in the above road map);
  • Step 2 Add compound D 1 (2.57g, 10mmol) to 60ml THF, add triethylamine (2.7mL, 20mmol) and Boc 2 O (3.32g, 15mmol), reflux for 6h, cool, spin dry, pass through a silica gel column 3.25 g of compound E 1 was obtained with a yield of 91%.
  • Step 3 Add compound E 1 (2.14g, 6mmol) to dry 50ml THF, under the protection of argon, cool to -78°C, add 4ml HMPA, and then slowly add 2M LDA in THF solution ( 8ml, 16mmol), stirred for 30-40min, then slowly heated to -30°C and stirred for 1h, then cooled to -78°C and added trimethylchlorosilane TMSCl (1.73g, 16mmol), slowly heated to -50°C, stirred 3h, pour into saturated ammonium chloride solution and return to room temperature, concentrate the solvent THF and add EA for extraction, dry the organic phase with anhydrous Na 2 SO 4 , spin off the solvent and vacuum dry, add 100ml of anhydrous DCM to the obtained oil Dissolve, cool to -15°C, add mCPBA (1.75g, 7.7mmol) under argon protection, stir for 1h and then warm to room temperature, add 50ml DCM and stir for 1h, then
  • Step 4 Dissolve compound F 1 (650 mg, 1.74 mmol) in 10 mL of dry THF, add gaseous HCl to saturation at room temperature and stir for 4 h, add 20 mL of dry ether, crystals precipitate out, filter to obtain compound T 1 cis-
  • the hydrochloride salt of 6-hydroxydesmethyltrifluoromethanone T 1 was 490 mg, and the yield was 90%.
  • the compound T 1 prepared above is the compound CF3 in the activity test.
  • mice were transferred to the laboratory 1 hour before the forced swim test (FST).
  • FST forced swim test
  • the test is carried out under normal lighting conditions and monitored by a digital video camera.
  • the mice were put into transparent glass cylinders (28.5 cm high and 14 cm in diameter) containing 20 cm of water (23 ⁇ 1°C).
  • the mice were trained for 6 minutes and then removed from the cylinder.
  • the mice were given a solvent (normal saline) control group, HNK, CF3, and then tested their immobile time after 1 hour and 7 days, where the immobile time refers to passive floating without other actions.
  • the hippocampal tissue samples from all mouse groups were separated, frozen in liquid nitrogen and stored at -80°C for use.
  • the sample was suspended in 8M urea (containing PBS (pH 8.0), 1x protease and phosphatase inhibitor mixture), and then sonicated with Sonics VCX-150 (Newtown, CT, USA). Subsequently, 14,000 g of the homogenate was centrifuged at 4°C for 30 minutes to remove cell debris. The supernatant was then collected in a new 1.5ml tube.
  • the protein concentration was determined by Nanodrop 2000 (Thermo Scientific, USA). According to the results of protein quantification, the concentration of all samples was adjusted to 1 ⁇ g/ ⁇ l.
  • the 100 ⁇ g protein of each sample from the same group was pooled, and a system with a total of 100 ⁇ g protein from each group was obtained.
  • the four combined samples were treated with 10mM DTT at 55°C for 60 minutes, and then at room temperature in the dark with 25mM IAA for 60 minutes.
  • Each combined sample was digested with 4 ⁇ g sequencing grade modified trypsin at 37°C for 1 hour, and then diluted with PBS (pH 8.0) to reach the final 1.0M urea concentration. Then, the sample continued to be digested overnight at 37°C. After digestion, the peptide was treated with 100% FA, and then desalted with peptide desalting spin columns (Waters, MC, USA). The peptide was dried with a vacuum concentrator, and finally dissolved in 200mM TEAB, and labeled with TMT working solution.
  • TMT mass tag labeling
  • TMT working solution Re-dissolve each vial of TMT with 40 ⁇ L 99.9% acetonitrile (ACN) to obtain a TMT working solution.
  • ACN acetonitrile
  • the peptides were then labeled with TMT working solution for 1 hour at room temperature.
  • Different groups were labeled with different TMT: the control group was labeled with TMT-127, the HNK group was labeled with TMT-128, and the CF3 group was labeled with TMT-131. After labeling, all peptides from the three groups were mixed, desalted, and dried as previously described.
  • the TMT-labeled peptides were separated according to the established components.
  • different sets of elution solutions were used for TMT-labeled samples.
  • the TMT-labeled peptide was separated in 300 ⁇ L of 0.1% formic acid, and then loaded on a spin column for reversed-phase fractionation.
  • the loaded peptide was eluted in 8 fractions with an ACN gradient buffer solution at pH 8.
  • the separated components were dried on a high-speed vacuum concentrator and stored at -80°C, waiting for LC-MS analysis.
  • the labeled separated fractions were reconstituted in 20 ⁇ L of 0.1% FA. Then, when equipped with C18 resin ( Peptides were separated on an UltiMate 300 RSLC nano System (Thermo Scientific, USA) of 5 ⁇ m; Varian, Lexington, MA) and a silica capillary column (75 ⁇ mID, 150 mm length, Upchurch, Oak Harbor, WA). A gradient with 0.1% FA and 5% ACN was run for 120 minutes at a fixed flow rate of 0.3 ⁇ L/min for relative quantification and target analysis. The ionized peptides were analyzed on a quadrupole-orbitrap mass spectrometer (Q-Exactive, Thermo Scientific, USA).
  • Proteome Discover 2.1 software uses the peak analysis and data processing of the Mus musculus database, in which the MS/MS spectrum of each nanoLC-MS/MS run is analyzed.
  • the parameters are set as follows: full trypsin specificity, allowing no more than two missed cuts, carbamoyl methylation (C) and MT plex (K and peptide N-terminus) as static modifications, and oxidation ( M) As a dynamic modification.
  • C carbamoyl methylation
  • MT plex K and peptide N-terminus
  • M oxidation
  • the precursor ion mass tolerance is set to 20 ppm
  • the fragment ion mass tolerance is set to 20 mmu.
  • Quantitative accuracy is reflected in the variability of protein ratios.
  • the fold change was calculated by the ratio of proteins labeled with TMT-128/TMT-127, TMT-131/TMT-128, and TMT-131/TMT-127.
  • the up-regulation and down-regulation thresholds were set to 1.2 (or 1.5) and 0.83 (or 0.67), respectively.
  • a forced swimming test is used to measure depression-like behaviors. Mice received 10 mg of HNK, CF3 by intragastric administration, and immobility time was measured after 1 hour and 7 days. The percentage of immobility time is expressed as: mean ⁇ SEM*p ⁇ 0.05, **p ⁇ 0.0 compared with pre-activation.
  • Each group N 8 saline: saline mice; HNK: 2R, 6R-hydroxynorchloramine treated mice; CF3, CF3 treated mice.
  • Ratio value higher than 1.2 is defined as an up-regulated protein
  • a Ratio value lower than 0.833 is defined as a down-regulated protein.
  • the control group there were 101 differentially expressed proteins in the CF3 treatment group, of which 39 differentially expressed proteins were co-expressed with the HNK treatment group.
  • C the expression abundance of 39 co-expressed differentially expressed proteins among the groups.
  • D the expression abundance of 60 co-expressed differentially expressed proteins among the groups.
  • A Compared with the control group, the enrichment analysis of the differentially expressed protein in the CF3 treatment group in the biological process.
  • B Compared with the control group, the molecular function enrichment analysis of the differentially expressed proteins in the CF3 treatment group.
  • C Compared with the HNK treatment group, the enrichment analysis of the differentially expressed protein in the CF3 treatment group in the biological process.
  • D the enrichment analysis of the differentially expressed proteins in the CF3 treatment group in terms of molecular function.
  • A Compared with the control group, the pathway enrichment analysis of differentially expressed proteins caused by CF3 treatment.
  • B Pathway analysis of differentially expressed protein caused by CF3 treatment compared with HNK treatment group.
  • CF3 compound Compared with HNK compound, the short-term effect of CF3 compound is equivalent to that of HNK, but HNK does not have long-term effect, it becomes invalid within 1 week and no longer has therapeutic effect.
  • the CF3 compound of the present application still has an antidepressant effect after 7 days, that is, it has a long-term effect.
  • the differential proteins produced by CF3 treatment are mainly enriched in lens development in camera-type eye, camera-type eye development, visual perception and other biological processes, as well as structural constituent of eye lens , Protein binding, poly(A)RNA binding and other molecular functions; compared with the HNK treatment group, the differential proteins produced by CF3 treatment are mainly enriched in biological processes such as transport, protein transport, lens development in camera-type eye, and Structural Consituent of Eye Lens, Protein Domain Specific Binding, Protein Binding and other molecular functions.
  • Pathway analysis results indicate that, compared with the control group, the differentially expressed protein produced by CF3 treatment is mainly enriched in spliceosome and mRNA splicing; compared with the HNK treatment group, the differentially expressed protein produced by CF3 treatment is mainly enriched in oxidative stress ,wnt signaling pathway, and long-term potentiation.
  • CF3 has a better long-term antidepressant effect than HNK.
  • CF3 treatment can cause the differential expression of a variety of proteins in the hippocampus of mice. The main pathway for its effect lies in spliceosome and mRNA splicing, compared to HNK.
  • the differentially expressed proteins produced by CF3 mainly focused on oxidative stress, long-term potentiation, and mitochondrial related effects.

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Abstract

Provided is a compound having a long-acting therapeutic effect. The compound can be used to prepare an antidepressant drug and drugs for anesthesia, analgesia, improvement of cognitive function, lung protection, amyotrophic lateral sclerosis or complex regional pain syndrome.

Description

一种长效化合物A long-acting compound 技术领域Technical field
本申请涉及药物领域，具体涉及一种治疗抑郁症、神经性和慢性疼痛，包括复杂性区域疼痛综合症(CRPS)的化合物。This application relates to the field of medicine, and specifically to a compound for treating depression, neuropathic and chronic pain, including complex regional pain syndrome (CRPS).
背景技术Background technique
***(ketamine)是临床常用的苯环己哌啶类静脉***物的代表,是近年来临床与基础研究发展较快的麻醉剂之一。在临床实践中,因为其具有诱导迅速、作用时间较短、苏醒较快、对呼吸和循环***影响较轻等特点,常用于满足儿科、产科、围手术期及特殊疾病患者的麻醉需求。Ketamine is a representative of intravenous anesthetics of phencyclidine commonly used in clinical practice, and it is one of the rapid development of clinical and basic research in recent years. In clinical practice, it is often used to meet the anesthesia needs of pediatrics, obstetrics, perioperative patients and patients with special diseases because of its characteristics such as rapid induction, shorter action time, faster awakening, and less impact on the respiratory and circulatory systems.
***最早于1962年合成，1965年用于人体，1970年被FDA正式批准用于临床。其典型的“分离麻醉”及短效确切的镇痛使得它曾红极一时，但是随后被发现精神方面的副作用及其他静脉***物的迅速发展使得***的临床使用大大减少。近10年来，随着对***用法用量的研究，及其抗炎，抗抑郁，神经保护、镇痛等的作用被发现，医学界对***的兴趣重新高涨。Ketamine was first synthesized in 1962, used in humans in 1965, and was officially approved by the FDA for clinical use in 1970. Its typical "separation anesthesia" and short-acting precise analgesia made it a smash hit, but then it was discovered that mental side effects and the rapid development of other intravenous anesthetics have greatly reduced the clinical use of ketamine. In the past 10 years, with the research on the usage and dosage of ketamine, and its anti-inflammatory, antidepressant, neuroprotective, analgesic and other effects have been discovered, the medical community has renewed interest in ketamine.
一直以来，***具有的强力镇痛，遗忘，同时能保留自主呼吸和气道保护性反射，保持血流动力学稳定等作用使得***在院前麻醉镇痛中的作用不容忽视。***同时具有神经毒性和神经保护作用，巨大的手术刺激理论上可能平衡麻醉的伤害，而***能够减轻手术伤害刺激引起的神经认知功能损害，***到底引起神经保护还是神经损害与使用***的剂量有直接相关性。For a long time, ketamine has strong analgesia, forgetfulness, while retaining spontaneous breathing and airway protective reflex, maintaining hemodynamic stability, etc., so that the role of ketamine in prehospital anesthesia and analgesia cannot be ignored. Ketamine has both neurotoxic and neuroprotective effects. The huge surgical stimulation may theoretically balance the damage of anesthesia, while ketamine can reduce the neurocognitive damage caused by surgical injury stimulation. Does ketamine cause neuroprotection or nerve damage and the dosage of ketamine? There is a direct correlation.
***对术后认知功能具有影响。有研究者对50例接受***麻醉的患儿进行测试后发现，***全麻可以降低患儿术后6h的认知功能，但对术后24h的认知功能无影响。Hudetz等发现在全麻诱导时给予0.5mg/kg***，能够降低心脏手术术后1周的术后认知功能障碍发生率，而这一作用可能与***的抗炎作用有关。近年来，众多的临床实验都证实，术中单次小剂量的应用***能够降低术后手术后认知功能障碍(POCD)发生率。Ketamine has an effect on postoperative cognitive function. Some researchers tested 50 children receiving ketamine anesthesia and found that general ketamine anesthesia can reduce the cognitive function of children 6 hours after surgery, but it has no effect on the cognitive function after 24 hours. Hudetz et al. found that giving 0.5 mg/kg ketamine during general anesthesia induction can reduce the incidence of postoperative cognitive dysfunction one week after cardiac surgery, and this effect may be related to the anti-inflammatory effect of ketamine. In recent years, numerous clinical trials have confirmed that a single small dose of ketamine during surgery can reduce the incidence of postoperative cognitive dysfunction (POCD).
***具有镇痛作用。亚麻醉剂量的***常被用于抗痛觉过敏，及急慢性疼痛的治疗。研究证实麻醉诱导前***盐水混合液漱口，能明显降低全麻气管插管引起的术后咽痛发生率及严重程度。术中阿片类药物使用使得术后阿片类药物镇痛用量增加，这种效应叫做阿片类药物耐受。而临床发现***的使用能够防止阿片类药物耐受，还能够逆转***耐受，增强***的镇痛效果。亦有研究证实小剂量***术中应用能够防止瑞芬太尼诱导的术后痛觉过敏。Cagla等对膝关节镜手术的病人术后静注***0.15mg/kg发现，***能显著提高术后镇痛满意度，且较***复合咪达***组镇静评分更低。Ketamine has an analgesic effect. Sub-anaesthetic doses of ketamine are often used for the treatment of hyperalgesia and acute and chronic pain. Studies have confirmed that gargle with ketamine salt water mixture before induction of anesthesia can significantly reduce the incidence and severity of postoperative sore throat caused by general anesthesia tracheal intubation. The use of opioids during surgery increases the amount of opioid analgesia after surgery. This effect is called opioid tolerance. It has been clinically found that the use of ketamine can prevent opioid tolerance and can also reverse morphine tolerance and enhance the analgesic effect of morphine. Studies have also confirmed that the intraoperative application of low-dose ketamine can prevent remifentanil-induced postoperative hyperalgesia. Cagla et al. found that after intravenous injection of ketamine 0.15 mg/kg in patients undergoing knee arthroscopy, ketamine can significantly improve the satisfaction of postoperative analgesia, and the sedation score is lower than that of the ketamine combined midazolam group.
***具有肺保护作用。近年来，***被发现具有显著地肺保护作用。有临床实验证实，胸科手术中单肺通气前经静脉和雾化都能够降低血中炎症因子的水平，而雾化吸入对心血管***和气道压更有好处，而肺通气侧雾化效果优于双肺雾化。***在临床中也常用于当常规治疗无效的致死性的哮喘发作的抢救，公认的其使用能够改善预后。Ketamine has lung protection. In recent years, ketamine has been found to have significant lung protection. Clinical experiments have confirmed that both intravenous and aerosolization before one-lung ventilation in thoracic surgery can reduce the level of inflammatory factors in the blood, and aerosol inhalation is more beneficial to the cardiovascular system and airway pressure, while the effect of aerosolization on the side of lung ventilation Better than double lung nebulization. Ketamine is also commonly used clinically in the rescue of fatal asthma attacks when conventional treatment is ineffective, and it is recognized that its use can improve the prognosis.
***具有抗抑郁的作用。2000年Berman等首次报道单次静脉注射亚麻醉剂量的***(0.5mg/kg，超过40min静脉注射)后72h内超过50％的患者汉密顿抑郁量表评分减低50％以上(详见：Berman RM，Cappiello A，Anand A，et al.Antidepressant effects of ketamine in depressed patients[J].Biol Psychiatry，2000，47(4)：351-354)。PaulR等发现相对于消旋***，S-***具有相似的抗抑郁作用，但精神方面副作用更小(详见：Paul R,Schaaff N,Padberg F,et al.Comparison of racemic ketamine and s-ketamine in treatment-resistant major depression:report of two cases[J].World j biol psychiatry,2009,10(3):241-244)。近几年，较多的动物和临床研究进一步证实***的抗抑郁效应。***也被用于抑郁病人电休克治疗的麻醉。2012年，美国政府健康及人类服务部、库珀卫生***和斯坦福研究院共同申请了申请号为CN 201280062294X，发明名称为(2R,6R)-羟基去甲***、(S)-脱氢去甲***以及(R,S)-***的其他立体异构脱氢和羟基化代谢物在治疗忧郁症和神经性疼痛中的应用的专利申请。CNS(中枢神经***)副作用与(R,S)-***对于NMDA受体的活性有关，在该申请中以***为基础，研究和合成了(2R,6R；2S,6S)-羟基去甲***(HNK)，该化合物对于NMDA受体没有活性，从而避免了可能的副作用，同时该化合物据称具 有治疗两极忧郁症、重度抑郁症、阿尔茨海默尔痴呆、肌萎缩侧索硬化症、复杂性区域疼痛综合症(CRPS)、慢性疼痛、或神经性疼痛的作用。Ketamine has an antidepressant effect. In 2000, Berman et al. reported for the first time that a single intravenous injection of sub-anaesthetic dose of ketamine (0.5 mg/kg, over 40 minutes intravenously) within 72 hours of more than 50% of patients with Hamilton Depression Scale score reduced by more than 50% (see: Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients [J]. Biol Psychiatry, 2000, 47(4): 351-354). PaulR et al. found that compared with racemic ketamine, S-ketamine has similar antidepressant effects, but has fewer mental side effects (see: Paul R, Schaaff N, Padberg F, et al. Comparison of racemic ketamine and s-ketamine in treatment-resistant major depression: report of two cases[J]. World j biological psychiatry,2009,10(3):241-244). In recent years, more animal and clinical studies have further confirmed the antidepressant effect of ketamine. Ketamine is also used as anesthesia for electroconvulsive therapy in depressed patients. In 2012, the U.S. Department of Health and Human Services, Cooper Health System and Stanford Research Institute jointly applied for application number CN 201280062294X, and the invention name is (2R,6R)-hydroxynorketamine, (S)-dehydronormethyl Patent application for the application of ketamine and other stereoisomeric dehydrogenation and hydroxylation metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. CNS (central nervous system) side effects are related to the activity of (R,S)-ketamine on NMDA receptors. In this application, based on ketamine, (2R,6R; 2S,6S)-hydroxynorketamine was researched and synthesized. (HNK), the compound has no activity on NMDA receptors, thus avoiding possible side effects. At the same time, the compound is said to have treatment for bipolar depression, major depression, Alzheimer’s dementia, amyotrophic lateral sclerosis, and complex The role of regional sexual pain syndrome (CRPS), chronic pain, or neuropathic pain.
我们在动物实验研究中发现，(2R,6R；2S,6S)-羟基去甲***(HNK)在给药后，药效持续时间并不长，1周内即失去疗效，这严重限制了治疗抑郁症时所希望的长效效果。因此如何对(2R,6R；2S,6S)-羟基去甲***(HNK)进行结构修饰，以获得更长药效的药物，将具有巨大的治疗潜力。We found in animal experiments that (2R, 6R; 2S, 6S)-hydroxynorketamine (HNK) does not last for a long time after administration, and it loses efficacy within 1 week, which severely limits the treatment The long-lasting effect desired in depression. Therefore, how to modify the structure of (2R, 6R; 2S, 6S)-hydroxynorketamine (HNK) to obtain a longer-acting drug will have great therapeutic potential.
发明内容Summary of the invention
本申请涉及一种具有抗抑郁、麻醉、镇痛、改善认知功能、肺保护、预防或治疗肌萎缩侧索硬化症或预防或治疗复杂性区域疼痛综合症的化合物。This application relates to a compound with antidepressant, anesthesia, analgesic, cognitive function improvement, lung protection, prevention or treatment of amyotrophic lateral sclerosis, or prevention or treatment of complex regional pain syndrome.
本申请的化合物与现有已知的HNK类化合物相比具有更长的药效时间，具体表现在HNK在一周内即代谢，失去疗效，而本申请的化合物药效时间可以持续1周以上。Compared with the existing known HNK compounds, the compound of the present application has a longer drug effect time, which is specifically manifested in that HNK is metabolized within one week and loses efficacy, while the drug effect time of the compound of the present application can last for more than one week.
本申请提供了如下式所示的化合物：This application provides a compound represented by the following formula:
Figure PCTCN2019091697-appb-000001
Figure PCTCN2019091697-appb-000001
其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
R 2独立地选自 R 2 is independently selected from
R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
本申请提供了如下式所示的化合物：This application provides a compound represented by the following formula:
Figure PCTCN2019091697-appb-000002
Figure PCTCN2019091697-appb-000002
其中among them
R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基、C 6-C 10芳基或单环或多环杂芳基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
本申请提供了如下所示的化合物：This application provides the following compounds:
Figure PCTCN2019091697-appb-000003
Figure PCTCN2019091697-appb-000003
其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
本申请提供了如下式所示的化合物：This application provides a compound represented by the following formula:
Figure PCTCN2019091697-appb-000004
Figure PCTCN2019091697-appb-000004
其中among them
R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基、C 6-C 10芳基或单环或多环杂芳基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
如前所述的化合物，其特征在于为如下化合物：The aforementioned compound is characterized by the following compounds:
Figure PCTCN2019091697-appb-000005
Figure PCTCN2019091697-appb-000005
如前所述的化合物，其特征在于为如下化合物：The aforementioned compound is characterized by the following compounds:
Figure PCTCN2019091697-appb-000006
Figure PCTCN2019091697-appb-000006
如前所述的化合物的制备方法，其特征在于制备路线如下:The preparation method of the compound as described above is characterized in that the preparation route is as follows:
Figure PCTCN2019091697-appb-000007
Figure PCTCN2019091697-appb-000007
如前所述的任一化合物在制备麻醉、镇痛、改善认知功能、肺保护、抗抑郁、肌萎缩侧索硬化症、复杂性区域疼痛综合症药物中的应用。The use of any of the aforementioned compounds in the preparation of drugs for anesthesia, analgesia, cognitive function improvement, lung protection, antidepressant, amyotrophic lateral sclerosis, and complex regional pain syndrome.
其中所述疼痛包括：慢性疼痛或神经性疼痛；抑郁症包括：两极忧郁症、重度抑郁症、伴随神经退行性疾病的忧郁症；改善认知功能包括预防或治疗阿尔茨海默尔痴呆、帕金森等。The pain includes: chronic pain or neuropathic pain; depression includes: bipolar depression, major depression, depression with neurodegenerative diseases; improvement of cognitive function includes prevention or treatment of Alzheimer’s dementia, Pa Jin Sen et al.
上述所有疾病，也涵盖了预防或治疗作用。All the diseases mentioned above also cover preventive or therapeutic effects.
本申请还提供了如下式所示的中间体化合物：The application also provides intermediate compounds represented by the following formula:
Figure PCTCN2019091697-appb-000008
Figure PCTCN2019091697-appb-000008
其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
R 5和R 6为保护基团； R 5 and R 6 are protecting groups;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
本申请还提供了如下式所示的中间体化合物：The application also provides intermediate compounds represented by the following formula:
Figure PCTCN2019091697-appb-000009
Figure PCTCN2019091697-appb-000009
其中R5和R6为H或保护基团；Wherein R5 and R6 are H or a protecting group;
或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
本申请还提供了如下式所示的中间体化合物：The application also provides intermediate compounds represented by the following formula:
Figure PCTCN2019091697-appb-000010
Figure PCTCN2019091697-appb-000010
本申请还提供了如下式所示的中间体化合物：The application also provides intermediate compounds represented by the following formula:
Figure PCTCN2019091697-appb-000011
Figure PCTCN2019091697-appb-000011
上述所有化合物的立体异构体包括对映异构体、非对映异构体。The stereoisomers of all the above compounds include enantiomers and diastereomers.
上述所有化合物在化合物以不同互变异构形式存在的情况下，本发明不限于任一种具体互变异构体，而是包括所有的互变异构体形式。When all the above-mentioned compounds exist in different tautomeric forms, the present invention is not limited to any specific tautomer, but includes all tautomeric forms.
上述所有化合物包括具有在化合物中出现的原子的所有可能的同位素的化合物。同位素包括具有相同原子序数但是不同质量数的那些原子。通过一般实例，在没有限制的情况下，氢的同位素包括氚和氘，并且碳的同位素包括 11C、 13C和 14C。 All the above-mentioned compounds include compounds having all possible isotopes of the atoms present in the compound. Isotopes include those atoms that have the same atomic number but different mass numbers. By general example, without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C, 13 C, and 14 C.
本申请还提供了一种药物组合物，本文中公开的化合物可以以纯化学品给予，但优选作为药物组合物给予。因此，本公开提供了包括化合物或药用盐连同至少一种药用载体的药物组合物。药物组合物可以包含化合物或盐作为唯一的活性剂，但是优选包含至少一种其他活性剂。在某些实施方式中，药物组合物是在单位剂型中包含约0.1mg至约1000mg、约1mg至约500mg、或约10mg至约200mg 的式I的化合物以及可选的约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg、或约200mg至约600mg的其他活性剂的口服剂型。The application also provides a pharmaceutical composition. The compound disclosed herein can be administered as a pure chemical, but is preferably administered as a pharmaceutical composition. Therefore, the present disclosure provides a pharmaceutical composition including a compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may include a compound or salt as the sole active agent, but preferably includes at least one other active agent. In certain embodiments, the pharmaceutical composition contains about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of the compound of formula I and optionally about 0.1 mg to about 2000 mg in a unit dosage form , About 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of other active agents.
本文中公开的化合物可以以包含常规药用载体的剂量单位制剂口服、局部、非肠道、通过吸入或喷雾、舌下、透皮、通过口腔给予、直肠、作为眼用溶液、或通过其它方式来给予。可以将药物组合物配制成任何药用形式，如：气雾剂、乳膏剂、凝胶剂、丸剂、胶囊剂、片剂、糖浆剂、透皮贴剂、或眼用溶液。诸如片剂和胶囊剂的一些剂型可以再分成包含诸如达到期望目的的有效量的适当量活性组分的适当剂量单位剂型。The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by oral cavity, rectal, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers Come and give. The pharmaceutical composition can be formulated into any medicinal form, such as aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or ophthalmic solution. Some dosage forms such as tablets and capsules can be subdivided into appropriate dosage unit dosage forms containing appropriate amounts of active ingredients such as effective amounts for the desired purpose.
载体包括赋形剂和稀释剂，并且必须具有足够高的纯度和十分低的毒性以使它们适于被给予待治疗的患者。载体可以是惰性的或其可以本身具有药用益处。Carriers include excipients and diluents, and must have sufficiently high purity and very low toxicity to make them suitable for administration to the patient to be treated. The carrier may be inert or it may have medicinal benefits by itself.
载体的种类包括但不限于：粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、滑润剂、防腐剂、稳定剂、表面活性剂、制片剂、以及润湿剂。一些载体可以列在多于一种的类别中，如：植物油可以在一些制剂中用作滑润剂并在其他制剂中用作稀释剂。示例性药用载体包括糖、淀粉、纤维素、西黄蓍胶粉(powdered tragacanth)、麦芽、明胶、滑石和植物油。可选的活性剂可以包括在药物组合物中，其基本上不影响本发明的化合物的生物功能。The types of carriers include, but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting Agent, and wetting agent. Some carriers can be listed in more than one category. For example, vegetable oils can be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutical carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils. An optional active agent may be included in the pharmaceutical composition, which does not substantially affect the biological function of the compound of the present invention.
本申请的化合物或盐可以是被给予的唯一活性剂或可以连同其他活性剂被给予。例如，本申请的化合物可以连同另一选自以下中的任一种的活性剂被给予：The compound or salt of the application may be the only active agent administered or may be administered in conjunction with other active agents. For example, the compound of the application can be administered together with another active agent selected from any of the following:
抗抑郁剂：草酸依地普仑、费洛克汀、帕罗西汀、度洛西汀、舍曲林、西酞普兰、丁氨苯丙酮、文拉法辛、度洛西汀、纳屈酮、米氮平、文拉法辛、阿托莫西汀、丁氨苯丙酮、多虑平、阿米替林、氯米帕明、去甲替林、丁螺环酮、阿立哌唑、氯氮平、克塞平、奥氮平、喹硫平、利培酮、齐拉西酮、酰胺咪嗪、加巴喷丁、拉莫三嗪、苯妥英、普瑞巴林、多奈哌齐、加兰他敏、美金刚、卡巴拉汀、高牛磺酸(tramiprosate)、或它们的药物活性盐或前药、或上述的组合； Antidepressants : edipram oxalate, felocktine, paroxetine, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, rice Zapine, venlafaxine, atomoxetine, bupropion, doxepine, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, chlorazide Ping, kesepin, olanzapine, quetiapine, risperidone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, donepezil, galantamine, memantine, Rivastigmine, tramiprosate, or their pharmaceutically active salts or prodrugs, or a combination of the above;
精神***症药物：阿立哌唑、鲁拉西酮、阿塞那平、氯氮平、齐拉西酮、利培酮、喹硫平、三氟啦嗪、奥氮平、克塞平、氟哌噻吨(flupentioxol)、佩吩嗪、氟哌丁苯、氯丙嗪、氟非那嗪、氟奋乃静、帕潘立酮； Schizophrenia drugs : aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, triflurazine, olanzapine, crexepin, Flupentixol (flupentioxol), perphenazine, haloperidol, chlorpromazine, fluphenazine, fluphenazine, paliperidone;
阿尔茨海默尔痴呆药物：多奈哌齐、卡巴拉汀、加兰他敏、美金刚；Alzheimer's dementia drugs: donepezil, rivastigmine, galantamine, memantine;
ALS药物：利鲁唑； ALS drug : riluzole;
疼痛药物：醋氨酚、阿斯匹林、NSAIDS，包括：双氯芬酸、二氟苯水杨酸、依托度酸、非诺洛芬、氟比洛芬、布洛芬、茚甲新、酮洛芬、酮咯酸、甲氯芬那酸、甲灭酸、美洛昔康、萘丁美酮、萘普生、奥沙普秦、苯基丁氮酮、吡罗昔康、舒林酸、Tolmetinopiods、Cox-2抑制剂如塞来昔布，以及麻醉疼痛药物如：丁丙诺啡、布托啡诺、可待因、二氢可待因酮、氢化***酮、羟甲左吗喃、哌替啶、***、***、纳布啡、氧可酮、氧***酮、镇痛新、丙氧芬、中枢性镇痛反胺苯环醇。 Pain drugs : acetaminophen, aspirin, NSAIDS, including: diclofenac, difluorobenzenesalicylic acid, etodolac, fenoprofen, flurbiprofen, ibuprofen, indoxine, ketoprofen , Ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, Tolmetinopiods, Cox -2 inhibitors such as celecoxib, and anesthetic pain drugs such as: buprenorphine, butorphanol, codeine, dihydrocodeinone, hydromorphone, hydroxymethyllevormorphan, pethidine , Methadone, morphine, nalbuphine, oxycodone, oxymorphone, analgesic new, propoxyphene, central analgesic tramadol.
其他活性剂的前述列表是示例性的而不是全面地包括。以上列表中未包含的其他的活性剂可以结合式I的化合物被给予。尽管在一些实施方式中，其他活性剂将以小于一般规定的剂量并且在一些情况下小于批准剂量的最小值给予，但是可以根据它的批准规定信息来给予其他活性剂。The foregoing list of other active agents is exemplary rather than comprehensive. Other active agents not included in the above list can be administered in combination with the compound of formula I. Although in some embodiments, the other active agent will be administered at a dose less than generally prescribed and in some cases less than the minimum approved dose, the other active agent may be administered according to its approved prescribed information.
本公开包括治疗抑郁症，尤其是治疗两极忧郁症和重度抑郁症的方法，特别是治疗难治性抑郁症(treatment-resistant depression)的方法，其中，化合物的有效量是有效缓解抑郁症状的最低剂量，其中，抑郁症状的缓解是达到在抑郁症状等级量表评分降低50％或更多，或在HRSD 17上小于或等于7的分数，或在QID-SR 16上小于或等于5、或在MADRS上小于或等于10。 The present disclosure includes methods for treating depression, especially bipolar depression and major depression, especially methods for treating treatment-resistant depression, wherein the effective amount of the compound is the lowest that is effective in alleviating the symptoms of depression Dose, where the relief of depressive symptoms is achieved by achieving a 50% or more reduction in the Depressive Symptom Rating Scale score, or a score less than or equal to 7 on HRSD 17 , or less than or equal to 5 on QID-SR 16 , or Less than or equal to 10 on MADRS.
本公开提供了有效减少疼痛(或镇痛)症状的量；其中，疼痛症状的减少是达到在疼痛等级量表上疼痛症状减少50％或更多。The present disclosure provides an amount effective to reduce pain (or analgesia) symptoms; wherein, the reduction of pain symptoms is to achieve a 50% or more reduction in pain symptoms on a pain rating scale.
术语约定：Terminology convention:
“立体异构体”是具有相同化学组成但原子或基团在空间中的排布不同的化合物。"Stereoisomers" are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.
“非对映异构体”是具有两个或更多手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体具有不同物理性能，例如：熔点、沸点、谱特性和反应活性。在拆分剂或色谱存在的情况下，使用诸如手性HPLC柱，可以在诸如电泳、结晶的高分辨分析步骤下分离非对映异构体的混合物。"Diastereoisomers" are stereoisomers that have two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics and reactivity. In the presence of a resolving agent or chromatography, a chiral HPLC column can be used to separate a mixture of diastereomers under high-resolution analysis steps such as electrophoresis and crystallization.
“对映异构体”指代彼此无重叠镜像的一种化合物的两个立体异构体。对映异构体的50:50的混合称为外消旋混合物或外消旋体，其在化学反应或处理过程中可以出现在已经没有立体选择性或立体定向性的情况下。"Enantiomers" refer to two stereoisomers of a compound that have no overlapping mirror images of each other. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can appear in a chemical reaction or process when there is no stereoselectivity or stereospecificity.
“烷基”包括支链和直链饱和脂肪族烃基两者，并具有指定数量的碳原子数量，一般1至约12个碳原子。如在本文中使用的术语C 1-C 6烷基表示具有1至约6个碳原子的烷基。当本文中结合另一基团使用C 0-C n烷基时，以(苯基)C 0-C 4烷基为例，指定的基团，在这种情况下，苯基是通过单个共价键(C 0)直接键合或通过具有指定的碳原子数(在这种情况下，1至约4个碳原子)的烷基链连接。烷基的实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、和仲戊基。 "Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups, and has a specified number of carbon atoms, generally 1 to about 12 carbon atoms. The term C 1 -C 6 alkyl as used herein means an alkyl group having 1 to about 6 carbon atoms. When a C 0 -C n alkyl group is used in conjunction with another group in this text, take (phenyl) C 0 -C 4 alkyl as an example, the designated group, in this case, the phenyl group is passed through a single co- The valence bond (C 0 ) is directly bonded or connected through an alkyl chain having the specified number of carbon atoms (in this case, 1 to about 4 carbon atoms). Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
“烯基”指包括一个或多个不饱和的碳-碳键的直链和支链烃链，碳-碳键可以出现在沿着链的任一稳定点。本文中所述的烯基通常具有2至约12个碳原子。优选烯基是低级烯基，那些烯基具有2至约8个碳原子，如：C 2-C 8、C 2-C 6、和C 2-C 4烯基。烯基的实例包括乙烯基、丙烯基、和丁烯基。 "Alkenyl" refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which can occur at any stable point along the chain. The alkenyl groups described herein generally have 2 to about 12 carbon atoms. Preferably, the alkenyl groups are lower alkenyl groups, those alkenyl groups having 2 to about 8 carbon atoms, such as: C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkenyl groups. Examples of alkenyl include vinyl, propenyl, and butenyl.
“烷氧基”是指具有通过氧桥连接的指定数量的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、3-己氧基、和3-甲基戊氧基。"Alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
术语“杂环”表示5-至8-元饱和环、部分不饱和环、或包含选自N、O和S的1至约4个杂原子且剩余的环原子是碳的芳族环，或是7至11元饱和环、部分不饱和环、或芳族杂环***和10至15-元三环***，该***包含选自N、O和S的多环***中的至少1个杂原子并且在多环***中的各环中包含独立地选自N、O和S的至多约4个杂原子。除非另外指明，否则杂环可以连接至它在任何杂原子和碳原子处取代并且产生稳定结构的基团。当指明时，本文中所述的杂环可以在碳或氮原子上被取代，只要得到的化合物是稳定的。可以可选地季铵化杂环中的氮原子。优选杂环基中杂原子的总数不大于4而且优选杂环基中S和O原子的总数不大于2，更优选不大于1。杂环基的实例包括：吡啶基、吲哚基、嘧啶基、哒嗪基(pyridizinyl)、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、***基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基(benz[b]thiophenyl)、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、二氢异吲哚基、5,6,7,8-四氢异喹啉、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡咯烷基、吗啉基、哌嗪基、哌啶基、和吡咯烷基。The term "heterocyclic ring" means a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing 1 to about 4 heteroatoms selected from N, O, and S and the remaining ring atoms are carbon, or It is a 7 to 11 membered saturated ring, partially unsaturated ring, or aromatic heterocyclic ring system and a 10 to 15-membered tricyclic ring system, which contains at least 1 heteroatom selected from the group consisting of N, O and S polycyclic ring systems And each ring in the polycyclic system contains up to about 4 heteroatoms independently selected from N, O, and S. Unless otherwise specified, the heterocyclic ring can be attached to a group where it is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic ring described herein may be substituted on a carbon or nitrogen atom as long as the resulting compound is stable. The nitrogen atom in the heterocyclic ring can optionally be quaternized. Preferably, the total number of heteroatoms in the heterocyclic group is not more than 4 and preferably the total number of S and O atoms in the heterocyclic group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio (benz[b]thiophenyl), isoquinolinyl, quinazolinyl, quinoxalinyl, Thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidine Group, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.
“芳基或杂芳基”表示包含选自N、O和S的1至4个、或优选1至3个杂原子并且剩余环原子为碳的稳定的5-或6-元单环或多环。当杂芳基中S和O原子 的总数超过1时，这些杂原子不彼此邻近。优选杂芳基中S和O原子的总数不大于2。尤其优选杂芳基中S和O原子的总数不大于1。可以可选地季铵化杂环中的氮原子。当指明时，这些杂芳基还可以用碳或非碳原子或基团取代。这种取代可以包括与可选地包含独立地选自N、O和S的1或2个杂原子的5至7-元饱和的环基的稠合，从而形成例如[1,3]二噁唑并[4,5-c]吡啶基。杂芳基的实例包括但不限于：吡啶基、吲哚基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、***基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。"Aryl or heteroaryl" means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl group is not more than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than one. The nitrogen atom in the heterocyclic ring can optionally be quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 5- to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O, and S, thereby forming, for example, [1,3]dioxin Azolo[4,5-c]pyridyl. Examples of heteroaryl groups include, but are not limited to: pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , And 5,6,7,8-tetrahydroisoquinoline.
“抑郁症”包括情绪低、活动兴趣下降、心理活动减缓或烦躁、食欲改变、注意力不集中或优柔寡断、过度内疚或自卑，并且在忧郁症、两极忧郁症、以及由于其它疾病或病况引起的情绪失常、物质引发的情绪失常和其他原因不明的情绪失常的情况下可能出现***意念，并且也可与各种其他精神性疾病(包括但不限于精神性失常、认知障碍、摄食障碍、焦虑症和人格障碍)共同存在。疾病的发展进程(longitudinal course)、病史、症状类型和病因有助于将情感性疾病的各种形式彼此区分开来。"Depression" includes low mood, decreased interest in activities, slowed or irritable mental activities, changes in appetite, inattention or indecision, excessive guilt or low self-esteem, and in depression, bipolar depression, and other diseases or conditions caused by Suicidal ideation may occur in the case of mood disorders, substance-induced mood disorders and other unexplained mood disorders, and can also be associated with various other mental illnesses (including but not limited to mental disorders, cognitive disorders, eating disorders, anxiety Syndrome and personality disorder) coexist. The progression of the disease (longitudinal course), medical history, type of symptoms, and etiology help to distinguish the various forms of affective diseases from each other.
“化合物的盐”是所公开的化合物的衍生物，其中，母体化合物通过制备无毒的酸或其碱加成盐改性，并且还指这些化合物和这些盐的药用溶剂化物，包括水合物。药用盐的实例包括但不限于：碱性残基如胺类的无机或有机酸加成盐；酸性残基如羧酸的碱或有机加成盐；等等，以及包括一种或多种上述盐的组合。药用盐包括诸如从无毒无机或有机酸形成的母体化合物的无毒盐和季铵盐。例如，无毒酸性盐包括衍生自无机酸的那些，例如：盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等；其他可接受的无机盐包括金属盐如：钠盐、钾盐、铯盐等；碱土金属盐如：钙盐、镁盐等，以及包括一种或多种上述盐的组合。"Salts of compounds" are derivatives of the disclosed compounds, wherein the parent compound is modified by preparing a non-toxic acid or its base addition salt, and also refers to these compounds and pharmaceutically acceptable solvates of these salts, including hydrates . Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues such as carboxylic acids; etc., and include one or more A combination of the above salts. Pharmaceutical salts include non-toxic salts and quaternary ammonium salts such as parent compounds formed from non-toxic inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids, such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, Cesium salt, etc.; alkaline earth metal salt such as calcium salt, magnesium salt, etc., and a combination including one or more of the above-mentioned salts.
化合物的有机盐包括由诸如乙酸、三氟乙酸、丙酸、丁二酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、对氨基苯磺酸、2-乙酸基苯酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙磺酸、HOOC-(CH 2) n-COOH(其中n为0至4)等的有机酸制备的盐；有机胺盐，如：三 乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N'-二苄基乙二胺盐等；和氨基酸盐，如：精氨酸盐、天冬氨酸盐、谷氨酸盐等，以及包括一种或多种上述盐的组合。 The organic salt of the compound includes compounds such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, hexanoic acid, maleic acid, hydroxymaleic acid , Phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methane Salts prepared from organic acids such as sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) n -COOH (where n is 0 to 4); organic amine salts, such as: triethylamine Salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.; and amino acid salt, such as arginine salt, aspartame Amino acid salts, glutamate salts, etc., and combinations including one or more of the foregoing salts.
附图说明Description of the drawings
图1小鼠抑郁样行为测试结果；Figure 1 Depression-like behavior test results in mice;
图2差异蛋白分析；Figure 2 Differential protein analysis;
图3差异蛋白的生物过程和分子功能的富集分析；Figure 3 Enrichment analysis of the biological processes and molecular functions of differential proteins;
图4差异表达蛋白的信号传导通路的富集分析；Figure 4 Enrichment analysis of signal transduction pathways of differentially expressed proteins;
图5-图10化合物的NMR谱图。Figure 5-Figure 10 NMR spectrum of the compound.
具体实施方式Detailed ways
实施例1：化合物制备方法Example 1: Compound preparation method
Figure PCTCN2019091697-appb-000012
Figure PCTCN2019091697-appb-000012
步骤一：由邻三氟甲基苯甲腈出发，按照经典的***药物合成法Calvin Stevens法(如上路线图所示)得到化合物D 1； Step 1: Starting from o-trifluoromethyl benzonitrile, compound D 1 is obtained according to the classic ketamine drug synthesis method Calvin Stevens method (shown in the above road map);
步骤二：将化合物D 1(2.57g，10mmol)加入60ml THF中，加入三乙胺(2.7mL,20mmol)及Boc 2O(3.32g,15mmol),回流6h，冷却，旋干，过硅胶柱得到化合物E 13.25克，产率91％。 1H NMR(300MHz,CDCl 3)：δ7.80(d,J＝8.1Hz,1H),7.66(d,J＝7.8Hz,1H),7.49(t,J＝7.5Hz,1H),7.22(t,J＝7.5Hz,1H),5.76(s, 1H),4.30(s,1H),3.46-3.42(m,1H),2.45–2.36(m,1H),2.35-2.22(m,1H),1.76–1.60(m,6H),1.21(s,9H). 13C NMR(75MHz,CDCl 3)：δ208.9,151.7,149.0,148.6,136.1，133.8,132.6,130.5,129.0,128.1,128.0,127.9,127.8,121.8,121.7,88.9,80.8,73.7,40.0,29.4,28.3,27.2,23.2； Step 2: Add compound D 1 (2.57g, 10mmol) to 60ml THF, add triethylamine (2.7mL, 20mmol) and Boc 2 O (3.32g, 15mmol), reflux for 6h, cool, spin dry, pass through a silica gel column 3.25 g of compound E 1 was obtained with a yield of 91%. 1 H NMR (300MHz, CDCl 3 ): δ 7.80 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.22 ( t,J=7.5Hz,1H),5.76(s, 1H), 4.30(s,1H),3.46-3.42(m,1H), 2.45–2.36(m,1H),2.35-2.22(m,1H) ,1.76–1.60(m,6H),1.21(s,9H). 13 C NMR(75MHz,CDCl 3 ): δ208.9,151.7,149.0,148.6,136.1,133.8,132.6,130.5,129.0,128.1,128.0,127.9 ,127.8,121.8,121.7,88.9,80.8,73.7,40.0,29.4,28.3,27.2,23.2;
步骤三：将化合物E 1(2.14g，6mmol)加入到干燥的50ml THF中，在氩气保护下，冷却至-78℃，加入4毫升HMPA,然后慢慢滴加入2M的LDA的THF溶液(8ml，16mmol)，搅拌30-40min，然后缓慢升温至-30℃搅拌1h，然后再冷却至-78℃并加入三甲基氯硅烷TMSCl(1.73g，16mmol)，缓慢升温至-50℃，搅拌3h，倒入饱和氯化铵溶液并恢复至室温，浓缩溶剂THF并加EA萃取，有机相加无水Na 2SO 4干燥，旋干溶剂并真空干燥，得到的油状物加入100ml无水的DCM溶解，冷却至-15℃，在氩气保护下，加入mCPBA(1.75g，7.7mmol)，搅拌1h后升温至室温，加入50ml DCM再搅拌1h，然后倒入饱和硫代硫酸钠和碳酸氢钠溶液(1:1)，用DCM萃取，旋干溶剂并真空干燥，得到的油状物再加入100mlTHF溶解，然后冷却至-5℃，加入四丁基氟化铵(3g，11.4mmol)，搅拌30min，加入饱和NaHCO 3溶液，用EA萃取，旋干溶剂并真空干燥，过硅胶柱，得到化合物F 1 1.34g产率60％。 1H NMR(300MHz,CDCl 3)：δ7.95(d,J＝7.8Hz,1H),7.68(d,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),7.40(t,J＝7.5Hz,1H),6.44(s,1H),4.12(dd,J＝11.7,6.8Hz,1H),3.87(d,J＝14.4Hz,1H),3.38(m,1H),2.36(m,1H),1.74(m,2H),1.72–1.63(m,6H),1.30(s,9H). 13C NMR(75MHz,CDCl 3)：208.2,153.2,131.8,131.5,128.7,128.3,79.4,72.8,66.3,60.4,40.2,28.2,27.9,19.6； Step 3: Add compound E 1 (2.14g, 6mmol) to dry 50ml THF, under the protection of argon, cool to -78℃, add 4ml HMPA, and then slowly add 2M LDA in THF solution ( 8ml, 16mmol), stirred for 30-40min, then slowly heated to -30°C and stirred for 1h, then cooled to -78°C and added trimethylchlorosilane TMSCl (1.73g, 16mmol), slowly heated to -50°C, stirred 3h, pour into saturated ammonium chloride solution and return to room temperature, concentrate the solvent THF and add EA for extraction, dry the organic phase with anhydrous Na 2 SO 4 , spin off the solvent and vacuum dry, add 100ml of anhydrous DCM to the obtained oil Dissolve, cool to -15°C, add mCPBA (1.75g, 7.7mmol) under argon protection, stir for 1h and then warm to room temperature, add 50ml DCM and stir for 1h, then pour into saturated sodium thiosulfate and sodium bicarbonate The solution (1:1) was extracted with DCM, spinned to dry the solvent and dried in vacuo, the resulting oil was dissolved in 100ml THF, then cooled to -5°C, tetrabutylammonium fluoride (3g, 11.4mmol) was added and stirred for 30min , Adding saturated NaHCO 3 solution, extracting with EA, spin-drying the solvent and vacuum drying, passing through a silica gel column to obtain 1.34 g of compound F 1 with a yield of 60%. 1 H NMR (300MHz, CDCl 3 ): δ7.95 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.40 ( t,J=7.5Hz,1H),6.44(s,1H),4.12(dd,J=11.7,6.8Hz,1H), 3.87(d,J=14.4Hz,1H), 3.38(m,1H), 2.36(m,1H),1.74(m,2H),1.72–1.63(m,6H),1.30(s,9H). 13 C NMR(75MHz,CDCl 3 ): 208.2, 153.2, 131.8, 131.5, 128.7, 128.3, 79.4, 72.8, 66.3, 60.4, 40.2, 28.2, 27.9, 19.6;
步骤四：将化合物F 1(650mg，1.74mmol)溶于10mL干燥的THF，室温下通入气体HCl至饱和并搅拌4h，加入20mL干燥的***，有晶体析出，过滤得到化合物T 1顺式-6-羟基去甲基三氟甲胺酮T 1的盐酸盐490mg，产率90％。 1H NMR(400MHz,CD 3OD)：δ8.12(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.97(t,J＝8.0Hz,1H),7.85(t,J＝8.0Hz,1H),4.28(dd,J 1＝11.6Hz,J 2＝6.8Hz,1H),3.46(dd,J 1＝14.4Hz,J 2＝2.8Hz,1H),2.07(m,1H),2.01–1.72(m,4H). 13C NMR(100MHz,CD 3OD)：205,133.7,131.1,130.9,128.9,128.8,127.6,73.1,67.0,60.7,44.2,38.6,38.3,29.4,28.9,18.6； Step 4: Dissolve compound F 1 (650 mg, 1.74 mmol) in 10 mL of dry THF, add gaseous HCl to saturation at room temperature and stir for 4 h, add 20 mL of dry ether, crystals precipitate out, filter to obtain compound T 1 cis- The hydrochloride salt of 6-hydroxydesmethyltrifluoromethanone T 1 was 490 mg, and the yield was 90%. 1 H NMR (400MHz, CD 3 OD): δ8.12 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.85 (t,J=8.0Hz,1H), 4.28(dd,J 1 =11.6Hz,J 2 ＝6.8Hz,1H), 3.46(dd,J 1 ＝14.4Hz,J 2 ＝2.8Hz,1H),2.07 (m,1H),2.01–1.72(m,4H). 13 C NMR (100MHz, CD 3 OD): 205,133.7,131.1,130.9,128.9,128.8,127.6,73.1,67.0,60.7,44.2,38.6,38.3, 29.4, 28.9, 18.6;
上述制备的化合物T 1即为活性测试中的化合物CF3。 The compound T 1 prepared above is the compound CF3 in the activity test.
实施例2：活性测试方法：Example 2: Activity test method:
1.强迫游泳实验1. Forced swimming experiment
在强迫游泳试验(FST)前1小时将小鼠转移到实验室。测试在正常光照条件下进行，并由数码摄像机监测。在试验期间，将小鼠分别放入含有20cm水(23±1℃)的透明玻璃圆筒(高28.5cm，直径14cm)中。第一天，将小鼠训练6分钟，然后从圆筒中取出。在第二天，给小鼠施用溶剂(生理盐水)对照组，HNK，CF3，然后在1小时和7天后测试其不动时间，其中不动时间是指被动漂浮没有其他动作。在整个6分钟游泳测试的最后4分钟内，通过Nodus***的EthoVision XT(Noldus，Netherland)记录不动时间(Castagné et al.,2011,Hajmirzaian et al.,2014,Porsolt et al.,1977)。每两到三次试验后，圆筒中的水要进行更换。游泳试验后，将小鼠从水中取出并在红外灯下晾干。The mice were transferred to the laboratory 1 hour before the forced swim test (FST). The test is carried out under normal lighting conditions and monitored by a digital video camera. During the test, the mice were put into transparent glass cylinders (28.5 cm high and 14 cm in diameter) containing 20 cm of water (23 ± 1°C). On the first day, the mice were trained for 6 minutes and then removed from the cylinder. On the second day, the mice were given a solvent (normal saline) control group, HNK, CF3, and then tested their immobile time after 1 hour and 7 days, where the immobile time refers to passive floating without other actions. In the last 4 minutes of the entire 6-minute swimming test, the immobile time was recorded through the EthoVision XT (Noldus, Netherlands) of the Nodus system (Castagné et al., 2011, Hajmirzaian et al., 2014, Porsolt et al., 1977). After every two to three tests, the water in the cylinder should be replaced. After the swimming test, the mice were taken out of the water and dried under infrared light.
2.蛋白质提取和消化2. Protein extraction and digestion
分离来自所有小鼠组的海马组织样品，在液氮中冷冻并储存在-80℃以备使用。样品在8M尿素(urea)(含有PBS(pH8.0)，1x蛋白酶和磷酸酶抑制剂混合物)中悬浮，然后用Sonics VCX-150(Newtown，CT，USA)超声处理。随后将匀浆物14,000g在4℃下离心30分钟以除去细胞碎片。然后将上清液收集到新的1.5ml管中。通过Nanodrop 2000(Thermo Scientific，USA)测定蛋白质浓度。根据蛋白质定量的结果，将所有样品的浓度调节至1μg/μl。汇集来自相同组的每个样品的100μg蛋白质，并获得来自每组的总共100μg蛋白质的***。将四个合并的样品用10mM DTT在55℃下处理60分钟，然后在室温下在黑暗中用25mM IAA处理60分钟。每个合并的样品用4μg测序级修饰的胰蛋白酶在37℃消化1小时，然后用PBS(pH 8.0)稀释以达到最终的1.0M尿素(urea)浓度。然后，样品继续在37℃下消化过夜。消化后，用100％FA处理肽，然后用肽脱盐旋转柱(peptide desalting spin columns)(Waters，MC，USA)脱盐。用真空浓缩器干燥肽，最后溶解在200mM TEAB中，用TMT工作溶液标记。The hippocampal tissue samples from all mouse groups were separated, frozen in liquid nitrogen and stored at -80°C for use. The sample was suspended in 8M urea (containing PBS (pH 8.0), 1x protease and phosphatase inhibitor mixture), and then sonicated with Sonics VCX-150 (Newtown, CT, USA). Subsequently, 14,000 g of the homogenate was centrifuged at 4°C for 30 minutes to remove cell debris. The supernatant was then collected in a new 1.5ml tube. The protein concentration was determined by Nanodrop 2000 (Thermo Scientific, USA). According to the results of protein quantification, the concentration of all samples was adjusted to 1μg/μl. The 100 μg protein of each sample from the same group was pooled, and a system with a total of 100 μg protein from each group was obtained. The four combined samples were treated with 10mM DTT at 55°C for 60 minutes, and then at room temperature in the dark with 25mM IAA for 60 minutes. Each combined sample was digested with 4μg sequencing grade modified trypsin at 37°C for 1 hour, and then diluted with PBS (pH 8.0) to reach the final 1.0M urea concentration. Then, the sample continued to be digested overnight at 37°C. After digestion, the peptide was treated with 100% FA, and then desalted with peptide desalting spin columns (Waters, MC, USA). The peptide was dried with a vacuum concentrator, and finally dissolved in 200mM TEAB, and labeled with TMT working solution.
3.Tandem mass tag(TMT)labeling(串联标记(TMT))3.Tandem mass tag (TMT) labeling (tandem tag (TMT))
将每小瓶TMT用40μL 99.9％乙腈(ACN)再溶解以获得TMT工作溶液。然后将肽用TMT工作溶液在室温下标记1小时。不同组用不同的TMT标记：对照组用TMT-127标记，HNK组用TMT-128标记，CF3组用TMT-131标记。标记后，将来自三个组的所有肽混合，脱盐，如前所述干燥。Re-dissolve each vial of TMT with 40 μL 99.9% acetonitrile (ACN) to obtain a TMT working solution. The peptides were then labeled with TMT working solution for 1 hour at room temperature. Different groups were labeled with different TMT: the control group was labeled with TMT-127, the HNK group was labeled with TMT-128, and the CF3 group was labeled with TMT-131. After labeling, all peptides from the three groups were mixed, desalted, and dried as previously described.
4.用高pH反相分离进行肽分级分离4. Peptide fractionation with high pH reverse phase separation
根据高pH反相方案，按照已建立的组分对TMT标记的肽进行分离。简而言之，由于不同的肽保留行为，不同组的洗脱溶液用于TMT标记的样品。将TMT标记的肽在300μL的0.1％甲酸中分离，然后加载到反相分级分离的旋转柱中。用pH8的ACN梯度缓冲溶液以8个级分洗脱加载的肽。将分离组分在高速真空浓缩器上干燥并储存在-80℃，等待LC-MS分析。According to the high pH reverse phase protocol, the TMT-labeled peptides were separated according to the established components. In short, due to different peptide retention behaviors, different sets of elution solutions were used for TMT-labeled samples. The TMT-labeled peptide was separated in 300 μL of 0.1% formic acid, and then loaded on a spin column for reversed-phase fractionation. The loaded peptide was eluted in 8 fractions with an ACN gradient buffer solution at pH 8. The separated components were dried on a high-speed vacuum concentrator and stored at -80°C, waiting for LC-MS analysis.
5.NanoLC-MS/MS和数据库搜索5.NanoLC-MS/MS and database search
标记的分离组分在20μL 0.1％FA中重构。然后，在配备有C18树脂(
Figure PCTCN2019091697-appb-000013
5μm；Varian，Lexington，MA)和二氧化硅毛细管柱(75μmID，150mm长度，Upchurch，Oak Harbor，WA)的UltiMate 300 RSLCnano System(Thermo Scientific，USA)上分离肽。将具有0.1％FA和5％ACN的梯度以0.3μL/min的固定流速运行120分钟，用于相对定量和目标分析。在四极杆-轨道阱质谱仪(Q-Exactive，Thermo Scientific，USA)上分析离子化的肽。Proteome Discover 2.1软件(Thermo Scientific，USA)用Mus musculus数据库的峰分析和数据处理，在该数据库中分析每个nanoLC-MS/MS运行(run)的MS/MS谱。对于蛋白质鉴定，参数设定如下：完全胰蛋白酶特异性，允许不超过两次漏切、氨甲酰甲基化(C)和MT plex(K和肽N-末端)作为静态修饰、和氧化(M)作为动态修饰。对于使用Orbitrap质量分析仪获得的所有MS数据，前体离子质量公差设定为20ppm，并且对于获得的所有MS/MS谱，碎片离子质量公差设定为20mmu。定量精确度以蛋白质比率变异性体现。通过用TMT-128/TMT-127，TMT-131/TMT-128，和TMT-131/TMT-127标记的蛋白质的比例计算倍数变化。上调和下调阈值分别设定为1.2(或1.5)和0.83(或0.67)。 The labeled separated fractions were reconstituted in 20 μL of 0.1% FA. Then, when equipped with C18 resin (
Figure PCTCN2019091697-appb-000013
Peptides were separated on an UltiMate 300 RSLC nano System (Thermo Scientific, USA) of 5 μm; Varian, Lexington, MA) and a silica capillary column (75 μmID, 150 mm length, Upchurch, Oak Harbor, WA). A gradient with 0.1% FA and 5% ACN was run for 120 minutes at a fixed flow rate of 0.3 μL/min for relative quantification and target analysis. The ionized peptides were analyzed on a quadrupole-orbitrap mass spectrometer (Q-Exactive, Thermo Scientific, USA). Proteome Discover 2.1 software (Thermo Scientific, USA) uses the peak analysis and data processing of the Mus musculus database, in which the MS/MS spectrum of each nanoLC-MS/MS run is analyzed. For protein identification, the parameters are set as follows: full trypsin specificity, allowing no more than two missed cuts, carbamoyl methylation (C) and MT plex (K and peptide N-terminus) as static modifications, and oxidation ( M) As a dynamic modification. For all MS data obtained using the Orbitrap mass analyzer, the precursor ion mass tolerance is set to 20 ppm, and for all MS/MS spectra obtained, the fragment ion mass tolerance is set to 20 mmu. Quantitative accuracy is reflected in the variability of protein ratios. The fold change was calculated by the ratio of proteins labeled with TMT-128/TMT-127, TMT-131/TMT-128, and TMT-131/TMT-127. The up-regulation and down-regulation thresholds were set to 1.2 (or 1.5) and 0.83 (or 0.67), respectively.
6.生物信息学分析6. Bioinformatics analysis
通过各种方法和方法分析蛋白质组学结果。DAVID版本6.7(https://david.ncifcrf.gov/)用于对差异表达蛋白质的功能类别和基因本体论(gene ontology，GO)注释富集分析进行分类。使用Venny 2.1版(http://bioinfogp.cnb.csic.es/tools/venny/index.html)对两只模型小鼠的海马蛋白质组进行逻辑分析。使用STRING版本10.5(https://string-db.org/)进行蛋白质-蛋白质相互作用网络分析。STRING生成的网络和wiki路径在Cytoscape 3.6.1版中可视化和编辑。Analyze proteomics results through various methods and methods. DAVID version 6.7 (https://david.ncifcrf.gov/) is used to classify the functional categories of differentially expressed proteins and gene ontology (gene ontology, GO) annotation enrichment analysis. Venny 2.1 (http://bioinfogp.cnb.csic.es/tools/venny/index.html) was used to analyze the hippocampal proteome of two model mice. Use STRING version 10.5 (https://string-db.org/) for protein-protein interaction network analysis. The network and wiki paths generated by STRING are visualized and edited in Cytoscape 3.6.1.
7.统计分析7. Statistical analysis
所有结果表示为平均值±SEM。N的数字在图例中给出。使用Prism(version 5.0,Graphpad software)和SPSS 19.0完成数据的统计分析。所有实验均使用Bonferroni's hoc测试进行参数测试(t检验，全双尾)或单因素方差分析(ANOVA)。p<0.05的值被认为是统计学上显著的。All results are expressed as mean±SEM. The number of N is given in the legend. Use Prism (version 5.0, Graphpad software) and SPSS 19.0 to complete the statistical analysis of the data. All experiments used Bonferroni's hoc test for parameter testing (t test, full two-tailed) or one-way analysis of variance (ANOVA). A value of p<0.05 is considered to be statistically significant.
实施例3：实验结果Example 3: Experimental results
1.小鼠抑郁样行为测试结果：1. Test results of depression-like behavior in mice:
如图1所示：As shown in Figure 1:
通过强迫游泳测试来测量抑郁样行为。小鼠通过胃内给药接受10mg HNK，CF3，并且在1小时和7天后测量不动时间。不动时间的百分比表示为：与预活性相比的平均值±SEM*p<0.05，**p<0.0。每组N＝8盐水：盐水小鼠；HNK：2R,6R-羟基去甲氯胺处理的小鼠；CF3，CF3处理的小鼠。A forced swimming test is used to measure depression-like behaviors. Mice received 10 mg of HNK, CF3 by intragastric administration, and immobility time was measured after 1 hour and 7 days. The percentage of immobility time is expressed as: mean ±SEM*p<0.05, **p<0.0 compared with pre-activation. Each group N=8 saline: saline mice; HNK: 2R, 6R-hydroxynorchloramine treated mice; CF3, CF3 treated mice.
2.差异蛋白分析:2. Differential protein analysis:
如图2所示：as shown in picture 2:
A,以0.833>Abundance Ratio>1.2为临界点，Ratio值高于1.2定义为上调蛋白，Ratio值低于0.833定义为下调蛋白。与对照组相比，CF3处理组有101个差异表达蛋白，其中有39个差异表达蛋白与HNK处理组有共表达。B,与HNK 处理组相比，CF3处理组有243个差异表达蛋白，其中有60个差异表达蛋白与CF3处理组有共表达。C,39个共表达的差异表达蛋白在各组间的表达丰度变化。D,60个共表达的差异表达蛋白在各组间的表达丰度变化。A. Taking 0.833>Abundance Ratio>1.2 as the critical point, a Ratio value higher than 1.2 is defined as an up-regulated protein, and a Ratio value lower than 0.833 is defined as a down-regulated protein. Compared with the control group, there were 101 differentially expressed proteins in the CF3 treatment group, of which 39 differentially expressed proteins were co-expressed with the HNK treatment group. B. Compared with the HNK treatment group, the CF3 treatment group has 243 differentially expressed proteins, of which 60 differentially expressed proteins are co-expressed with the CF3 treatment group. C, the expression abundance of 39 co-expressed differentially expressed proteins among the groups. D, the expression abundance of 60 co-expressed differentially expressed proteins among the groups.
3.差异蛋白生物过程和分子功能的富集分析3. Enrichment analysis of differential protein biological processes and molecular functions
如图3所示：As shown in Figure 3:
A,与对照组相比，CF3处理组的差异表达蛋白在生物过程上的富集分析。B,与对照组相比，CF3处理组的差异表达蛋白在分子功能上的富集分析。C,与HNK处理组相比，CF3处理组的差异表达蛋白在生物过程上的富集分析。D,CF3处理组的差异表达蛋白在分子功能上的富集分析。A, Compared with the control group, the enrichment analysis of the differentially expressed protein in the CF3 treatment group in the biological process. B, Compared with the control group, the molecular function enrichment analysis of the differentially expressed proteins in the CF3 treatment group. C, Compared with the HNK treatment group, the enrichment analysis of the differentially expressed protein in the CF3 treatment group in the biological process. D, the enrichment analysis of the differentially expressed proteins in the CF3 treatment group in terms of molecular function.
4.差异表达蛋白的通路富集分析4. Pathway enrichment analysis of differentially expressed proteins
如图4所示：As shown in Figure 4:
A,与对照组相比，CF3处理引起的差异表达蛋白的通路富集分析。B,与HNK处理组相比，CF3处理引起的差异表达蛋白的通路分析。A, Compared with the control group, the pathway enrichment analysis of differentially expressed proteins caused by CF3 treatment. B, Pathway analysis of differentially expressed protein caused by CF3 treatment compared with HNK treatment group.
如上所述的结果可以看出：The above results can be seen:
1.与HNK化合物相比，CF3化合物的短期效果与HNK相当，而HNK并不具备长效效果，在1周内即失效，不再具有治疗效果。而本申请的CF3化合物在7天后仍然具有抗抑郁的效果，即其起到了长效的效果。1. Compared with HNK compound, the short-term effect of CF3 compound is equivalent to that of HNK, but HNK does not have long-term effect, it becomes invalid within 1 week and no longer has therapeutic effect. The CF3 compound of the present application still has an antidepressant effect after 7 days, that is, it has a long-term effect.
2.venny分析结果提示，与对照组相比，CF3处理组有101个差异表达蛋白，其中有39个差异表达蛋白与HNK处理组有共表达；与HNK处理组相比，CF3处理组共有243个差异表达蛋白，其中有60个差异表达蛋白与CF3处理组有共表达。2. The results of venny analysis indicated that compared with the control group, there were 101 differentially expressed proteins in the CF3 treatment group, of which 39 differentially expressed proteins were co-expressed with the HNK treatment group; compared with the HNK treatment group, the CF3 treatment group had a total of 243 Among them, 60 differentially expressed proteins were co-expressed with the CF3 treatment group.
3.GO分析结果显示，与对照组相比，CF3处理产生的差异蛋白主要富集在lens development in camera-type eye，camera-type eye development，visual perception等生物过程上，以及structural constituent of eye lens，protein binding，poly(A)RNA binding等分子功能上；与HNK处理组相比，CF3处理产生的差异蛋白主要富集在transport，protein transport，lens development in camera-type eye 等生物过程上，以及structural constituent of eye lens，protein domain specific binding，protein binding等分子功能上。3. GO analysis results show that, compared with the control group, the differential proteins produced by CF3 treatment are mainly enriched in lens development in camera-type eye, camera-type eye development, visual perception and other biological processes, as well as structural constituent of eye lens , Protein binding, poly(A)RNA binding and other molecular functions; compared with the HNK treatment group, the differential proteins produced by CF3 treatment are mainly enriched in biological processes such as transport, protein transport, lens development in camera-type eye, and Structural Consituent of Eye Lens, Protein Domain Specific Binding, Protein Binding and other molecular functions.
4.通路分析结果提示，与对照组相比，CF3处理产生的差异表达蛋白主要富集在spliceosome和mRNA splicing上；对HNK处理组相比，CF3处理产生的差异表达蛋白主要富集在oxidative stress,wnt signaling pathway,以及long-term potentiation上。4. Pathway analysis results indicate that, compared with the control group, the differentially expressed protein produced by CF3 treatment is mainly enriched in spliceosome and mRNA splicing; compared with the HNK treatment group, the differentially expressed protein produced by CF3 treatment is mainly enriched in oxidative stress ,wnt signaling pathway, and long-term potentiation.
总之，CF3与HNK相比，具有更好的长期抗抑郁效果，CF3处理能引起小鼠海马组织多种蛋白的差异表达，其发挥作用的主要通路在于spliceosome和mRNA splicing上，而相比于HNK处理组，CF3产生的差异表达蛋白主要集中在oxidative stress，long-term potentiation，以及线粒体相关作用上。这些结果综合说明CF3在机体中可能主要通过发挥剪接体的作用来影响oxidative stress，long-term potentiation，以及线粒体电子传递链来发挥抗抑郁的作用的。In short, CF3 has a better long-term antidepressant effect than HNK. CF3 treatment can cause the differential expression of a variety of proteins in the hippocampus of mice. The main pathway for its effect lies in spliceosome and mRNA splicing, compared to HNK. In the treatment group, the differentially expressed proteins produced by CF3 mainly focused on oxidative stress, long-term potentiation, and mitochondrial related effects. These results comprehensively indicate that CF3 may affect oxidative stress, long-term potentiation, and the mitochondrial electron transport chain to play an antidepressant effect in the body through the role of spliceosome.

Claims (14)

  1. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100001
    Figure PCTCN2019091697-appb-100001
    其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
    R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
    R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
    R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  2. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100002
    Figure PCTCN2019091697-appb-100002
    其中among them
    R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基、C 6-C 10芳基或单环或多环杂芳基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
    R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  3. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100003
    Figure PCTCN2019091697-appb-100003
    其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
    R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
    R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl;
    R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  4. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100004
    Figure PCTCN2019091697-appb-100004
    其中among them
    R 3独立地选自C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8酰基、C 6-C 10芳基或单环或多环杂芳基； R 3 is independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 acyl, C 6 -C 10 aryl or monocyclic or polycyclic Heteroaryl
    R 4独立地选自C 1-C 8酰基、芳基酰基或杂芳基酰基； R 4 is independently selected from C 1 -C 8 acyl, aryl acyl or heteroaryl acyl;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  5. 如权利要求1-4任一项所述的化合物，其特征在于为如下化合物：The compound of any one of claims 1-4, which is characterized as the following compound:
    Figure PCTCN2019091697-appb-100005
    Figure PCTCN2019091697-appb-100005
  6. 如权利要求1-4任一项所述的化合物，其特征在于为如下化合物：The compound of any one of claims 1-4, which is characterized as the following compound:
    Figure PCTCN2019091697-appb-100006
    Figure PCTCN2019091697-appb-100006
  7. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100007
    Figure PCTCN2019091697-appb-100007
    其中m为0-3的整数，n为0-4的整数；Where m is an integer of 0-3, and n is an integer of 0-4;
    R 1和R 2独立地选自H、卤素、羟基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、单-和二-C 1-C 4烷基氨基、C 1-C 2卤代烷基、C 1-C 2卤代烷氧基、C 6-C 10芳基或单环或多环杂芳基中的1种或多种； R 1 and R 2 are independently selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino , 1 or more of C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 6 -C 10 aryl, or monocyclic or polycyclic heteroaryl;
    R5和R6为保护基团；R5 and R6 are protecting groups;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  8. 如下式所示的化合物：Compounds represented by the following formula:
    Figure PCTCN2019091697-appb-100008
    Figure PCTCN2019091697-appb-100008
    其中R 5和R 6为H或保护基团； Wherein R 5 and R 6 are H or a protecting group;
    或上述化合物的盐、立体异构体、互变异构体。Or salts, stereoisomers, or tautomers of the above compounds.
  9. 一种如下所示化合物：A compound shown below:
    Figure PCTCN2019091697-appb-100009
    Figure PCTCN2019091697-appb-100009
  10. 一种如下所示化合物：A compound shown below:
    Figure PCTCN2019091697-appb-100010
    Figure PCTCN2019091697-appb-100010
  11. 一种药物组合物，其特征在于包括权利要求1-10任一项所述的化合物以及药学上可接受的载体。A pharmaceutical composition characterized by comprising the compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier.
  12. 根据权利要求11所述的药物组合物，其特征在于：载体包括赋形剂和稀释剂。The pharmaceutical composition according to claim 11, wherein the carrier includes excipients and diluents.
  13. 根据权利要求11所述的药物组合物，其特征在于：载体是粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、滑润剂、防腐剂、稳定剂、表面活性剂、制片剂、以及润湿剂中的一种或多种。The pharmaceutical composition according to claim 11, wherein the carrier is a binder, buffer, coloring agent, diluent, disintegrant, emulsifier, flavoring agent, glidant, lubricant, preservative, One or more of stabilizers, surfactants, tableting, and wetting agents.
  14. 根据权利要求13所述的药物组合物，其特征在于：所述载体为糖、淀粉、纤维素、麦芽、明胶、滑石以及植物油中的一种或多种。The pharmaceutical composition according to claim 13, wherein the carrier is one or more of sugar, starch, cellulose, malt, gelatin, talc and vegetable oil.
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