CN110538169B - Application of long-acting compound in preparation of medicine - Google Patents

Application of long-acting compound in preparation of medicine Download PDF

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CN110538169B
CN110538169B CN201910526556.7A CN201910526556A CN110538169B CN 110538169 B CN110538169 B CN 110538169B CN 201910526556 A CN201910526556 A CN 201910526556A CN 110538169 B CN110538169 B CN 110538169B
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周强
叶涛
李书鹏
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Abstract

The application provides an application of a compound with a long-acting treatment effect in preparing a medicament, and the compound can be used for preparing medicaments for resisting depression, anesthesia, analgesia, improving cognitive function, lung protection, amyotrophic lateral sclerosis and complex regional pain syndrome.

Description

Application of long-acting compound in preparation of medicine
Technical Field
The application relates to the field of medicines, in particular to application of a compound for treating depression, neuropathic pain and chronic pain, including Complex Regional Pain Syndrome (CRPS) in preparation of medicines.
Background
Ketamine (ketamine) is a representative of the phencyclidine intravenous anesthetic commonly used in clinic, and is one of the anesthetics with rapid development of clinical and basic research in recent years. In clinical practice, it is often used to meet the anesthesia needs of pediatric, obstetric, perioperative and patients with specific diseases because of its rapid induction, short duration of action, rapid recovery, and minimal impact on the respiratory and circulatory systems.
Ketamine was first synthesized in 1962, used in humans in 1965, and officially approved by the FDA in 1970 for clinical use. Its typical "split anesthesia" and short-term, definitive analgesia makes it ever red for the best, but subsequent discovery of psychiatric side effects and rapid development of other intravenous anesthetic drugs has led to a substantial reduction in the clinical use of ketamine. In the last 10 years, with the research on the usage amount of ketamine and the discovery of its anti-inflammatory, antidepressant, neuroprotective, analgesic, etc. effects, the medical community has been increasingly interested in ketamine.
In the past, ketamine has the functions of strongly relieving pain and forgetting, simultaneously keeping spontaneous respiration and airway protective reflex, keeping hemodynamic stability and the like, so that the effect of ketamine in pre-hospital anesthesia pain relief cannot be ignored. Ketamine has both neurotoxic and neuroprotective effects, a huge surgical stimulus theoretically may balance the anesthetic injury, and ketamine can alleviate the neurocognitive function impairment caused by surgical injury stimuli, and whether ketamine alone causes neuroprotection or neuroimpairment is directly related to the dose of ketamine used.
Ketamine has an effect on post-operative cognitive function. After 50 patients receiving ketamine anesthesia are tested by researchers, the ketamine general anesthesia can reduce the cognitive function of the patients after 6 hours of operation, but has no influence on the cognitive function of the patients after 24 hours of operation. Hudetz et al found that the administration of 0.5mg/kg ketamine at the time of general anesthesia induction reduced the incidence of post-operative cognitive dysfunction for 1 week after cardiac surgery, which may be related to the anti-inflammatory effects of ketamine. In recent years, numerous clinical trials have demonstrated that the application of ketamine in a single small intraoperative dose can reduce the incidence of postoperative post-operative cognitive dysfunction (POCD).
Ketamine has analgesic effect. Sub-anesthetic doses of ketamine are often used for anti-hyperalgesia, and the treatment of acute and chronic pain. Research proves that the ketamine saline mixed solution before anesthesia induction can obviously reduce the incidence and severity of postoperative pharyngalgia caused by general anesthesia tracheal intubation. The use of opioids during surgery increases the amount of opioid analgesic used after surgery, an effect called opioid tolerance. The clinical findings show that the use of ketamine can prevent opioid tolerance, reverse morphine tolerance and enhance morphine analgesic effect. There are also studies demonstrating that the use of small doses of ketamine in surgery can prevent remifentanil-induced post-operative hyperalgesia. Cagla and the like find that ketamine can remarkably improve postoperative analgesic satisfaction by 0.15mg/kg of ketamine after being injected statically for patients with knee arthroscopic surgery, and the ketamine has lower sedation score than ketamine compound midazolam group.
Ketamine has a lung protective effect. In recent years, ketamine has been found to have a significant lung protective effect. Clinical experiments prove that the level of inflammatory factors in blood can be reduced by veins and atomization before single lung ventilation in the thoracic surgery, the atomization inhalation is more beneficial to a cardiovascular system and airway pressure, and the atomization effect of the lung ventilation side is superior to that of double-lung atomization. Ketamine is also commonly used in the clinic for the rescue of fatal asthma attacks where conventional therapy is ineffective, and its use is well recognized as improving prognosis.
Ketamine has antidepressant effect. Berman et al first reported in 2000 that more than 50% of patients had a reduction in the Hamilton depression scale by more than 50% within 72h after a single intravenous dose of ketamine (0.5mg/kg, more than 40min intravenous injection) (see, for example, Berman RM, Capphiello A, and A, et al, anti effects of ketamine in compressed patents [ J ]. Biol Psychiatry, 2000, 47 (4): 351-354). PaulR et al found that S-ketamine had similar antidepressant effects but less psychologically side effects than racemic ketamine (see: Paul R, Schaaff N, Padberg F, et al. Complex of scientific ketamine and S-ketamine in vitro therapeutic major expression: report of two cases [ J ]. Worldj diol kinase, 2009,10(3): 241-244). In recent years, more animal and clinical studies have further demonstrated the antidepressant effect of ketamine. Ketamine is also used in anesthesia for the treatment of electrical shock in depressed patients.
In 2012, the U.S. department of government health and human services, cooper' S sanitation system, and stanford research institute filed patent applications with application number CN 201280062294X entitled (2R,6R) -hydroxynorketamine, (S) -dehydronorketamine, and the use of other stereoisomeric dehydro-and hydroxylated 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 which application (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) was studied and synthesized on the basis of ketamine, which compound is inactive on NMDA receptors, thereby avoiding possible side effects, while the compound is said to have effects on the treatment of bipolar depression, major depression, Alzheimer' S dementia, amyotrophic lateral sclerosis, Complex Regional Pain Syndrome (CRPS), chronic pain, or neuropathic pain.
In animal experiments, we found that (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) has a short duration of drug effect after administration, i.e., the effect is lost within 1 week, which severely limits the long-lasting effect expected in the treatment of depression. Therefore, the structural modification of (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) to obtain a drug with longer drug effect has great treatment potential.
Disclosure of Invention
The application relates to application of a compound with the functions of resisting depression, anaesthetizing, easing pain, improving cognitive function, protecting lungs, preventing or treating amyotrophic lateral sclerosis or complex regional pain syndrome in preparation of a medicament.
Compared with the existing known HNK compounds, the compound has longer drug effect time, which is particularly shown in that HNK is metabolized and loses curative effect within one week, and the drug effect time of the compound can last for more than 1 week.
The present application provides compounds of the formula:
Figure GDA0002228272240000031
wherein m is an integer of 0 to 3 and n is an integer of 0 to 4;
R1and R2Independently selected from H, halogen, hydroxy, amino, cyano, C1-C4Alkyl radical, C1-C4Alkoxy, mono-and di-C1-C4Alkylamino radical, C1-C2Haloalkyl, C1-C2Haloalkoxy, C6-C 101 or more of aryl or monocyclic or polycyclic heteroaryl;
R2is independently selected from
R3Independently selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8An acyl group;
R4independently selected from C1-C8Acyl, arylacyl or heteroarylacyl;
or a salt, stereoisomer, tautomer of the foregoing compound.
The present application provides compounds of the formula:
Figure GDA0002228272240000041
wherein
R3Independently selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8Acyl radical, C6-C10Aryl or monocyclic or polycyclic heteroaryl;
R4independently selected from C1-C8Acyl, arylacyl or heteroarylacyl;
or a salt, stereoisomer, tautomer of the foregoing compound.
The present application provides compounds as shown below:
Figure GDA0002228272240000042
wherein m is an integer of 0 to 3 and n is an integer of 0 to 4;
R1and R2Independently selected from H, halogen, hydroxy, amino, cyano, C1-C4Alkyl radical, C1-C4Alkoxy, mono-and di-C1-C4Alkylamino radical, C1-C2Haloalkyl, C1-C2Haloalkoxy, C6-C 101 or more of aryl or monocyclic or polycyclic heteroaryl;
R3independently selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8An acyl group;
R4independently selected from C1-C8Acyl, arylacyl or heteroarylacyl;
or a salt, stereoisomer, tautomer of the foregoing compound.
The present application provides compounds of the formula:
Figure GDA0002228272240000051
wherein
R3Independently selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8Acyl radical, C6-C10Aryl or monocyclic or polycyclic heteroaryl;
R4independently selected from C1-C8Acyl, arylacyl or heteroarylacyl;
or a salt, stereoisomer, tautomer of the foregoing compound.
The compound as described above, characterized by being the following compound:
Figure GDA0002228272240000052
the compound as described above, characterized by being the following compound:
Figure GDA0002228272240000053
the preparation method of the compound is characterized by comprising the following steps:
Figure GDA0002228272240000061
use of any of the compounds as described above for the manufacture of a medicament for anaesthesia, analgesia, cognitive function improvement, lung protection, antidepressant, amyotrophic lateral sclerosis, complex regional pain syndrome.
Wherein the pain comprises: chronic pain or neuropathic pain; depression includes: bipolar depression, major depression, melancholia accompanying neurodegenerative diseases; improving cognitive function includes preventing or treating alzheimer's dementia, parkinson's disease, and the like.
All of the above diseases, either prophylactic or therapeutic, are also contemplated.
The present application also provides intermediate compounds represented by the formula:
Figure GDA0002228272240000062
wherein m is an integer of 0 to 3 and n is an integer of 0 to 4;
R1and R2Independently selected from H, halogen, hydroxy, amino, cyano, C1-C4Alkyl radical, C1-C4Alkoxy, mono-and di-C1-C4Alkylamino radical, C1-C2Haloalkyl, C1-C2Haloalkoxy, C6-C 101 or more of aryl or monocyclic or polycyclic heteroaryl;
R5and R6Is a protecting group;
or a salt, stereoisomer, tautomer of the foregoing compound.
The present application also provides intermediate compounds represented by the formula:
Figure GDA0002228272240000071
wherein R5 and R6 are H or a protecting group;
or a salt, stereoisomer, tautomer of the foregoing compound.
The present application also provides intermediate compounds represented by the formula:
Figure GDA0002228272240000072
the present application also provides intermediate compounds represented by the formula:
Figure GDA0002228272240000073
stereoisomers of all the above compounds include enantiomers, diastereomers.
Where all of the above compounds exist in different tautomeric forms, the invention is not limited to any one particular tautomer, but includes all tautomeric forms.
All of the compounds described above include compounds having all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include11C、13C and14C。
the present application also provides a pharmaceutical composition, and the compounds disclosed herein can be administered as pure chemicals, but preferably as a pharmaceutical composition. Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt in combination with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may comprise the compound or salt as the only active agent, but preferably comprises at least one other active agent. In certain embodiments, the pharmaceutical composition is an oral dosage form comprising from about 0.1mg to about 1000mg, from about 1mg to about 500mg, or from about 10mg to about 200mg of a compound of formula I, and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of another active agent in a unit dosage form.
The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by buccal administration, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers. The pharmaceutical composition may be formulated in any pharmaceutical form, such as: aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit forms containing appropriate quantities of the active component, such as an effective amount to achieve the desired purpose.
Carriers include excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient to be treated. The carrier may be inert or it may itself have a pharmaceutical benefit.
Types of vectors include, but are not limited to: binders, buffering agents, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some vectors may be listed in more than one category, such as: vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder (powdered tragacanth), malt, gelatin, talc and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially affect the biological function of the compounds of the present invention.
The compounds or salts of the present application may be the only active agent administered or may be administered in conjunction with other active agents. For example, a compound of the present application may be administered in conjunction with another active agent selected from any one of the following:
antidepressants: escitalopram oxalate, feloxetine, paroxetine, duloxetine, sertraline,Citalopram, bupropion, venlafaxine, duloxetine, naltrexone, mirtazapine, venlafaxine, atomoxetine, bupropion, doxepin, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, clozapine, clozepine, olanzapine, quetiapine, risperidone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, donepezil, galantamine, memantine, rivastigmine, homotaurine (tramiprisate), or pharmaceutically active salts or prodrugs thereof, or combinations of the foregoing;
schizophrenia medicine: aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine, olanzapine, closerpine, flupentixol (flupenttioxol), phenoxazine, haloperidol, chlorpromazine, fluphenazine, paliperidone;
alzheimer dementia drugs: donepezil, rivastigmine, galantamine, memantine;
ALS medicine: riluzole;
pain medicine: acetaminophen, aspirin, NSAIDS, including: diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetinopodies, Cox-2 inhibitors such as celecoxib, and narcotic pain medications such as: buprenorphine, butorphanol, codeine, dihydrocodeinone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, analgesin, propoxyphene, central analgesic tramadol.
The foregoing list of other active agents is exemplary and not comprehensive. Other active agents not included in the above list may be administered in conjunction with the compound of formula I. Although in some embodiments, the other active agent will be administered at a dose less than the generally prescribed dose and in some cases less than the minimum approved dose, the other active agent may be administered according to its approved regulatory information.
The disclosure includes methods of treating depression, particularly bipolar depression and major depression, particularly treatment-refractory depression (treatment-refractory depression), wherein an effective amount of the compound is the lowest dose effective to alleviate the symptoms of depression, wherein the alleviation of the symptoms of depression is by a 50% or more reduction on the depression symptom scale or at an HRSD17A fraction of above 7 or below, or in QID-SR16Or less than or equal to 5, or less than or equal to 10 on the MADRS.
The present disclosure provides an amount effective to reduce pain (or analgesia) symptoms; wherein the reduction in pain symptoms is to achieve a 50% or greater reduction in pain symptoms on a pain scale.
The terminology convention:
"stereoisomers" are compounds having the same chemical composition but differing arrangements of atoms or groups in space.
"diastereoisomers" are stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example: melting point, boiling point, spectral characteristics and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis, crystallization, using, for example, chiral HPLC columns in the presence of resolving agents or chromatography.
"enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur already without stereoselectivity or stereospecificity during chemical reactions or processing.
"alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C as used herein1-C6Alkyl represents an alkyl group having 1 to about 6 carbon atoms. When C is used in combination with another group herein0-CnWhen alkyl, with (benzene)Group) C0-C4Alkyl is an example, a group being specified, in which case phenyl is via a single covalent bond (C)0) Either directly bonded or attached through an alkyl chain having the indicated 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.
"alkenyl" refers to straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, such as: c2-C8、C2-C6And C2-C4An alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.
"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.
The term "heterocycle" means a 5-to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing from 1 to about 4 heteroatoms selected from N, O and S with the remaining ring atoms being carbon, or a 7-to 11-membered saturated, partially unsaturated, or aromatic heterocyclic system and a 10-to 15-membered tricyclic ring system containing at least 1 heteroatom in a polycyclic ring system selected from N, O and S and containing up to about 4 heteroatoms independently selected from N, O and S in each ring of the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on carbon or nitrogen atoms, as long as the resulting compounds are stable. The nitrogen atoms in the heterocycle may optionally be quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not more than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl (benz [ b ] thiophenyl), isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7, 8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.
"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 being carbon. 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 no greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. The nitrogen atoms in the heterocycle may 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, a [1,3] dioxazolo [4,5-c ] pyridyl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7, 8-tetrahydroisoquinoline.
"depression" includes low mood, decreased activity interest, reduced or irritated psychological activity, altered appetite, inattention or feeble feelings of decline, excessive guilt or self-mutilation, and suicidal ideation may occur in cases of depression, bipolar depression, and mood disorders due to other diseases or conditions, substance-induced mood disorders, and other unexplained mood disorders, and may also co-exist with various other psychiatric disorders including but not limited to psychotic disorders, cognitive disorders, feeding disorders, anxiety disorders, and personality disorders. The progression of the disease (longitudinal course), history, type of symptoms and etiology help to distinguish the various forms of affective disease from each other.
"salts of compounds" are derivatives of the disclosed compounds wherein the parent compound is modified by the preparation of non-toxic acid or base addition salts thereof, and also refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; base or organic addition salts of acidic residues such as carboxylic acids; and the like, as well as combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non-toxic acidic salts include those derived from inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; other acceptable inorganic salts include metal salts such as: sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as: calcium salts, magnesium salts, and the like, as well as combinations comprising one or more of the foregoing salts.
Organic salts of the compounds include those formed from compounds such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, methanesulfonic, ethanesulfonic, benzenesulfonic, sulfanilic, 2-acetoxybenzoic, fumaric, p-toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC- (CH)2)nSalts prepared with organic acids such as-COOH (wherein n is 0 to 4); organic amine salts, such as: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, and the like; and amino acid salts, such as: arginine salts, aspartic acid salts, glutamic acid salts, and the like, as well as combinations comprising one or more of the foregoing salts.
Drawings
FIG. 1 results of a mouse Depression-like behavior test;
FIG. 2 differential protein analysis;
FIG. 3 enrichment analysis of biological processes and molecular functions of differential proteins;
FIG. 4 enrichment analysis of the signaling pathway of differentially expressed proteins;
FIG. 5-NMR spectra of the compounds of FIG. 10.
Detailed Description
Example 1: process for the preparation of compounds
Figure GDA0002228272240000121
The method comprises the following steps: starting from o-trifluoromethylbenzonitrile, compound D is obtained according to the classical ketamine drug synthesis method CalvinStevens method (the preparation route is shown above)1；
Step two: compound D1(2.57g, 10mmol) was added to 60mL THF, triethylamine (2.7mL,20mmol) and Boc2O (3.32g,15mmol), refluxing for 6h, cooling, spin-drying, passing through silica gel column to obtain compound E13.25 g, 91% yield.1H NMR(300MHz,CDCl3)：7.80(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,CDCl3)：208.9,151.7,149.0,148.6,136.1，133.8,132.6,130.5,129.0,128.1,128.0,127.9,127.8,121.8,121.7,88.9,80.8,73.7,40.0,29.4,28.3,27.2,23.2；
Step three: reacting a compound E1(2.14g, 6mmol) is added to dry 50ml THF, under the protection of argon, cooled to-78 ℃, 4 ml HMPA is added, then 2M THF solution of LDA (8ml, 16mmol) is slowly added dropwise, stirred for 30-40min, then slowly heated to-30 ℃ and stirred for 1h, then cooled to-78 ℃ again and trimethylchlorosilane TMSCl (1.73g, 16mmol) is added, slowly heated to-50 ℃, stirred for 3h, saturated ammonium chloride solution is poured and returned to room temperature, solvent THF is concentrated and EA is added for extraction, anhydrous Na is added to organic phase2SO4Drying, spin-drying the solvent and vacuum drying, dissolving the obtained oil in 100ml of anhydrous DCM, cooling to-15 deg.C, adding mCPBA (1.75g, 7.7mmol) under argon protection, stirring for 1hWarming to room temperature, adding 50ml DCM and stirring for 1h, then pouring saturated sodium thiosulfate and sodium bicarbonate solution (1:1), extracting with DCM, spin-drying the solvent and vacuum-drying, adding 100ml THF to dissolve the oily substance, then cooling to-5 deg.C, adding tetrabutylammonium fluoride (3g, 11.4mmol), stirring for 30min, adding saturated NaHCO3Extracting the solution with EA, spin-drying the solvent and vacuum-drying, passing through a silica gel column to obtain compound F11.34g yield 60%.1H NMR(300MHz,CDCl3)：7.95(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,CDCl3)：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 four: compound F1(650mg, 1.74mmol) in 10mL dry THF, saturated with gaseous HCl at room temperature and stirred for 4h, 20mL dry ether was added and crystals precipitated and filtered to give Compound T1cis-6-HydroxydemethyltrifluoromethyltrifluoromethyltrifluoromethylketoneT1Hydrochloride salt 490mg, yield 90%.1H NMR(400MHz,CD3OD)：8.12(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,J1＝11.6Hz,J2＝6.8Hz,1H),3.46(dd,J1＝14.4Hz,J2＝2.8Hz,1H),2.07(m,1H),2.01–1.72(m,4H).13C NMR(100MHz,CD3OD)：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；
Compound T prepared as described above1This is the compound CF3 in the activity test.
Example 2: activity test method:
1. forced swimming experiment
Mice were transferred to the laboratory 1 hour prior to the Forced Swim Test (FST). The test was performed under normal lighting conditions and monitored by a digital video camera. During the experiment, the mice were placed individually in clear glass cylinders (height 28.5cm, diameter 14cm) containing 20cm of water (23. + -. 1 ℃). On the first day, mice were trained for 6 minutes and then removed from the cylinders. On the next day, mice were administered a solvent (saline) control group, HNK, CF3, and then tested for immobility time after 1 hour and 7 days, where immobility time means passive floating with no other action. The immobility time was recorded by EthoVision XT (Noldus, Netherland) by the Nodus system during the last 4 minutes of the entire 6-minute swimming test (castagne et al, 2011, hajmirzaan et al, 2014, Porsolt et al, 1977). After every two to three tests, the water in the cylinder was replaced. After the swimming test, the mice were taken out of the water and dried under an infrared lamp.
2. Protein extraction and digestion
Hippocampal tissue samples from all mouse groups were isolated, frozen in liquid nitrogen and stored at-80 ℃ for use. The samples were suspended in 8M urea (urea) (containing PBS (pH8.0), 1 Xprotease and phosphatase inhibitor cocktail) and then sonicated with sonic VCX-150(Newtown, CT, USA). The homogenate, 14,000g, was then centrifuged at 4 ℃ for 30 minutes to remove cell debris. The supernatant was then collected into a new 1.5ml tube. The protein concentration was determined by Nanodrop 2000(ThermoScientific, USA). The concentration of all samples was adjusted to 1. mu.g/. mu.l as a result of protein quantification. 100 μ g of protein from each sample of the same group were pooled and a total of 100 μ g of protein from each group was obtained for the system. The four pooled samples were treated with 10mM DTT at 55 ℃ for 60 minutes, then 25mM IAA at room temperature in the dark for 60 minutes. Each pooled sample was digested with 4. mu.g of sequencing grade modified trypsin at 37 ℃ for 1 hour, then diluted with PBS (pH8.0) to reach the final 1.0M urea (urea) concentration. The sample then continued to digest overnight at 37 ℃. After digestion, the peptides were treated with 100% FA and then desalted using peptide desalting spin columns (Waters, MC, USA). The peptide was dried using a vacuum concentrator and finally dissolved in 200mM TEAB and labeled with TMT working solution.
Tandem Mass Tag (TMT) labeling (Tandem tag (TMT))
Each vial of TMT was redissolved with 40 μ L of 99.9% Acetonitrile (ACN) to obtain a TMT working solution. The peptides were then labeled with TMT working solution at room temperature for 1 hour. Different groups are labeled with different TMTs: the control group was labeled with TMT-127, the HNK group with TMT-128 and the CF3 group with TMT-131. After labeling, all peptides from the three groups were mixed, desalted and dried as before.
4. Peptide fractionation with high pH reverse phase separation
The TMT-labelled peptides were separated according to the established fractions according to a high pH reverse phase protocol. Briefly, different sets of elution solutions were used for TMT-labeled samples due to different peptide retention behavior. The TMT-labeled peptide was separated in 300. mu.L of 0.1% formic acid and then loaded on a reverse phase fractionation spin column. The loaded peptide was eluted in 8 fractions with ACN gradient buffer at pH8. The separated fractions were dried on a high-speed vacuum concentrator and stored at-80 ℃ for analysis by LC-MS.
NanoLC-MS/MS and database search
The labeled fractions were reconstituted in 20 μ L of 0.1% FA. Then, the resin is prepared with C18 resin (C18)
Figure GDA0002228272240000151
5 μm; varian, Lexington, Mass.) and silica capillary columns (75. mu. mID, 150mm length, Upchurch, Oak Harbor, WA) on an Ultimate 300RSLCnano System (Thermo Scientific, USA). The gradient with 0.1% FA and 5% ACN was run at a fixed flow rate of 0.3 μ L/min for 120 minutes for relative quantification and target analysis. The ionized peptides were analyzed on a quadrupole-orbitrap mass spectrometer (Q-exact, Thermo Scientific, USA). ProteomeDiscoverer 2.1 software (Thermo Scientific, USA) MS/MS spectra for each nanoLC-MS/MS run (run) were analyzed in a Mus musculus database for peak analysis and data processing. For protein identification, the parameters were set as follows: complete trypsin specificity, allowing no more than two leakages, carbamoylmethylation (C) and MT plex (K and peptide N-terminus) as static modifications, and oxidation (M) as dynamic modifications. The precursor ion mass tolerance was set to 20ppm for all MS data obtained using the Orbitrap mass analyser and the fragment ion mass tolerance was set to 20mmu for all MS/MS spectra obtained. Quantitative accuracy is expressed in protein ratio variability. Fold changes were calculated by using the ratios of TMT-128/TMT-127, TMT-131/TMT-128, and TMT-131/TMT-127 labeled proteins. The up and down thresholds are set to 1.2 (or 1.5) and 0.83 (or 0.67), respectively.
6. Bioinformatics analysis
Proteomic results are analyzed by various methods and methods. DAVID version 6.7(https:// DAVID. ncifcrf. gov /) was used to classify functional classes of differentially expressed proteins and Gene Ontology (GO) annotated enrichment assays. Logical analysis of hippocampal proteomes of two model mice was performed using version Venny 2.1 (http:// bioinfogp. cnb. csic. es/tools/Venny/index. html). Protein-protein interaction network analysis was performed using STRING version 10.5(https:// STRING-db.org /). The STRING generated network and wiki paths are visualized and edited in Cytoscape version 3.6.1.
7. Statistical analysis
All results are expressed as mean ± SEM. The number of N is given in the legend. Statistical analysis of the data was done using Prism (version5.0, Graphpad software) and SPSS 19.0. All experiments were either parametric (t-test, full two-tailed) or one-way analysis of variance (ANOVA) using the Bonferroni' shoc test. A value of p <0.05 was considered statistically significant.
Example 3: results of the experiment
1. Results of mouse depression-like behavior test:
as shown in fig. 1:
depression-like behavior was measured by a forced swim test. Mice received 10mg of hnk, CF3 by intragastric administration and the 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 to preactivity. Each group N-8 brine:
saline mice; HNK: 2R, 6R-hydroxynorchloramine-treated mice; CF3, CF3 treated mice.
2. Differential protein analysis:
as shown in fig. 2:
a, taking 0.833> Absundance Ratio >1.2 as a critical point, defining that the Ratio value is higher than 1.2 as up-regulated protein, and defining that the Ratio value is lower than 0.833 as down-regulated protein. Compared with the control group, the CF 3-treated group had 101 differentially expressed proteins, of which 39 were co-expressed with the HNK-treated group. B, there were 243 differentially expressed proteins in the CF3 treated group compared to the HNK treated group, of which 60 were co-expressed with CF3 treated group. C, the expression abundance of 39 co-expressed differentially expressed proteins varied among the groups. D, the expression abundance of 60 co-expressed differentially expressed proteins varied between groups.
3. Enrichment analysis of differential protein biological processes and molecular functions
As shown in fig. 3:
a, enrichment analysis of the differentially expressed proteins in the CF3 treated group in biological processes compared to the control group. And B, compared with a control group, the CF3 treatment group is used for the enrichment analysis of the molecular functions of the differential expression protein. C, enrichment analysis of differentially expressed proteins in biological processes in CF 3-treated group compared to HNK-treated group. D, enrichment analysis of differentially expressed proteins in the CF 3-treated group on molecular function.
4. Pathway enrichment analysis of differentially expressed proteins
As shown in fig. 4, there is shown:
pathway enrichment analysis of differentially expressed proteins from CF3 treatment compared to control; and pathway enrichment analysis of differentially expressed proteins from CF3 treatment compared to HNK treated group.
The results described above show that:
1. compared with the HNK compound, the CF3 compound has the short-term effect which is equivalent to the HNK compound, while the HNK does not have the long-term effect, is ineffective within 1 week and does not have the treatment effect any more. The CF3 compound of the present application still has an antidepressant effect after 7 days, i.e. it exerts a long-lasting effect.
The venny analysis results suggested that there were 101 differentially expressed proteins in the CF 3-treated group compared to the control group, of which 39 were co-expressed with the HNK-treated group; the CF3 treated group had 243 differentially expressed proteins compared to the HNK treated group, of which 60 were co-expressed with CF3 treated group.
GO analysis shows that compared with a control group, the differential protein generated by CF3 treatment is mainly enriched on biological processes such as lentivirus in camera-type eye, camera-type eye level, visual performance and molecular functions such as structural compliance of eye lens, protein binding, poly (A) RNA binding; compared with the HNK treatment group, the differential protein produced by the CF3 treatment is mainly enriched on the biological processes of transport, protein transport, lens degradation in camera-type eye and the like, and the molecular functions of structural coherence of eye lens, protein domain specific binding, protein binding and the like.
4. The results of the pathway analysis suggested that the differentially expressed proteins from CF3 treatment were predominantly enriched on the sporosomes and mRNA spicing compared to the control group; the differentially expressed proteins produced by CF3 treatment were mainly enriched in oxidative stress, wnt signaling pathway, and long-term stress compared to the HNK treated group.
In conclusion, CF3 has a better long-term antidepressant effect compared to HNK, CF3 treatment resulted in differential expression of multiple proteins in mouse hippocampal tissues, the main pathways for their action being on heliceosome and mRNA helicing, whereas CF3 produced differentially expressed proteins mainly focused on oxidative stress, long-termptention, and mitochondria-related effects compared to the HNK treated group. These results taken together suggest that CF3 may affect the oxidative stress, long-term stress, and the mitochondrial electron transport chain in the body primarily by acting as a spliceosome to exert an antidepressant effect.

Claims (3)

1. The application of a long-acting compound in the preparation of antidepressant drugs is characterized in that: the compound has the following structural formula:
Figure FDA0002518858490000011
2. the use according to claim 1, wherein the depression disorder comprises: bipolar depression, major depression and/or depression associated with neurodegenerative diseases.
3. Use according to any one of claims 1-2, characterized in that the medicament is formulated as a pill, capsule, tablet or syrup.
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