CN112521358B

CN112521358B - Application of long-acting low-addiction HNK derivative in preparation of medicines

Info

Publication number: CN112521358B
Application number: CN202010892676.1A
Authority: CN
Inventors: 李书鹏; 周强
Original assignee: Shenzhen Ruijian Biotechnology Co ltd
Current assignee: Shenzhen Ruijian Biotechnology Co ltd
Priority date: 2020-08-31
Filing date: 2020-08-31
Publication date: 2021-10-08
Anticipated expiration: 2040-08-31
Also published as: CN112521358A

Abstract

The invention relates to the field of medicines, and relates to application of a low-addiction HNK derivative in preparation of medicines, in particular to application of a low-addiction HNK derivative in preparation of medicines for treating or preventing depression, including Complex Regional Pain Syndrome (CRPS) and other diseases. The compound has a structure shown in a formula I, and can be used for preparing a medicament for preventing or treating depression, anesthesia, analgesia, cognitive function improvement, lung protection, amyotrophic lateral sclerosis or complex regional pain syndrome. Compared with the existing known HNK compounds, the compound of the invention has longer drug effect time, and the compound of the invention basically does not generate addiction.

Description

Application of long-acting low-addiction HNK derivative in preparation of medicines

Technical Field

The invention relates to the field of medicines, in particular to application of a low-addiction HNK derivative in treating or preventing depression, including Complex Regional Pain Syndrome (CRPS) and other diseases.

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, was used in humans in 1965, and was officially approved by the FDA for clinical use in 1970. 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 the anti-inflammatory, antidepressant, neuroprotection, analgesic and other effects, the medical community has a rising interest in ketamine.

In the past, ketamine has the functions of strongly relieving pain and forgetting, simultaneously keeping spontaneous respiration and airway protective reflex, keeping hemodynamics stable and the like, so that the effect of ketamine in the pre-hospital anesthesia analgesia is not negligible. Ketamine has both neurotoxic and neuroprotective effects.

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. In recent years, numerous clinical experiments have demonstrated that the application of ketamine in a single small intraoperative dose can reduce the incidence of postoperative cognitive dysfunction.

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 trachea cannula. 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. Studies have also demonstrated 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 the postoperative analgesic satisfaction of patients after knee arthroscopic surgery by 0.15mg/kg of ketamine after 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 over 50% of patients had a more than 50% reduction in the Hamilton depression scale score over 72 hours after a single intravenous injection of a sub-anesthetic dose of ketamine (0.5 mg/kg). In recent years, more animal and clinical studies have further demonstrated the antidepressant effect of ketamine. Chloraminoketone is also used in anesthesia for the treatment of electroconvulsive shock in depressed patients.

Application No. CN 201280062294X, a patent application entitled (2R,6R) -hydroxynorketamine, (S) -dehydronorketamine, and other stereoisomeric dehydrogenized and hydroxylated metabolites of (R, S) -ketamine for use in the treatment of depression and neuropathic pain, discloses that CNs (central nervous system) side effects are related to the activity of (R, S) -ketamine at NMDA receptors, in which (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) was studied and synthesized based on ketamine, and was inactive at NMDA receptors, thereby avoiding possible side effects, while being said to have the ability to treat bipolar depression, major depression, alzheimer dementia, amyotrophic lateral sclerosis, Complex Regional Pain Syndrome (CRPS), Chronic pain, or neuropathic pain.

In experimental studies, we have found that (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) does not have a long duration of action after administration and is essentially inactive for 1 week, which severely limits the long-lasting effect desired in the treatment of depression. Meanwhile, the research of the inventor also finds that certain addiction can be generated when HNK is applied, and adverse effects are caused on the mind and body of a patient. Therefore, the structural modification of (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) to obtain a drug with longer drug effect and lower addiction has great treatment potential.

Disclosure of Invention

The present invention relates to a compound having antidepressant, anxiety-and post-traumatic stress syndrome-improving, anesthetic, analgesic, cognitive function-improving, pulmonary protection, prevention or treatment of amyotrophic lateral sclerosis or complex regional pain syndrome.

Compared with the prior known HNK compounds, the compound of the invention has longer drug effect time, specifically, the HNK is metabolized within one week, and has no activity, while the drug effect time of the compound of the invention can last for more than 1 week, specifically, more than 7 days, more than 10 days, more than 14 days, and the like. Moreover, the compounds of the present invention are substantially free of addiction, which is 2 times, 5 times, 10 times, or 20 times less addictive than HNK-based compounds.

The invention provides a compound, a salt of the compound, a stereoisomer or a tautomer of the compound, wherein the compound has a structure shown in a formula I:

wherein:

wherein m is an integer of 0 to 3 and n is an integer of 0 to 4;

R₁and R₂Each independently selected from H, halogen, hydroxy, amino, cyano, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Heterocyclic radical, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted mono-and di-C₁-C ₆1 or more of alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R₃is halogen;

R₄selected from H, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₈An acyl group, a substituted or unsubstituted arylacyl group, or a substituted or unsubstituted heteroarylacyl group;

R₅selected from substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀A heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group;

R₆selected from H, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₁₀Heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted C₁-C₈An acyl group, a substituted or unsubstituted arylacyl group, or a substituted or unsubstituted heteroarylacyl group;

the substitution is by OH; NH (NH)₂；C₁-C₁₀Alkyl, alkenyl or alkynyl; c₁-C₁₀An alkylamino group; mercapto group; c₁-C₁₀An alkylmercapto group; c₁-C₂₀An alkoxy group; c₁-C₁₀A carbonyl group; c₃-C₁₀A cycloalkyl group; a 3-10 membered heterocyclyl having one or more heteroatoms selected from N, S, O, P; c₆-C₂₀An aryl group; c₂-C₂₀A heteroaryl group; nitro cyano, or halogen.

Preferably, the compound as described above, characterized in that it has the structure of formula II:

preferably, the compound as described above, characterized in that it has the structure of formula III:

wherein p is an integer of 0 to 3.

Preferably, the compound as described above, characterized in that it has the structure of formula IV:

wherein p is an integer of 0 to 3.

Preferably, the compound as described above, characterized by being a compound represented by:

the invention also provides a compound, a salt of a compound, a stereoisomer, or a tautomer of a compound having the structural formula:

wherein R is₇Is H or a protecting group.

Preferably, the compound, salt, stereoisomer, or tautomer of the compound, as described above, is characterized by the following structure:

or

The present invention also provides a pharmaceutical composition characterized by comprising a compound, a salt of a compound, a stereoisomer, or a tautomer of any one of claims 1 to 8, optionally further comprising a pharmaceutically acceptable carrier.

The invention also provides a preparation method of the compound, which is characterized by comprising the following steps:

use of any of the compounds as described hereinbefore for the manufacture of a medicament for anaesthesia, analgesia, cognitive function improvement, lung protection, antidepressant, anxiety and post-traumatic stress syndrome, amyotrophic lateral sclerosis, complex regional pain syndrome.

Wherein the pain comprises: chronic pain or neuropathic pain; depression includes: bipolar depression, severe depression; improving anxiety and post-traumatic stress syndrome; 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.

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 invention also provides a pharmaceutical composition, the compounds disclosed herein may 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, buffers, 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. An optional active agent may be included in the pharmaceutical composition which does not substantially affect the activity of the compounds of the invention.

The compounds or salts of the present invention may be the only active agent administered or may be administered in conjunction with other active agents. For example, a compound of the invention 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 thereof;

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 invention 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 a dose effective to reduce depression symptoms, wherein the reduction in depression symptoms is a reduction of up to 50% or more of the symptoms identified on a melancholia symptom grade scale, or in 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 invention provides an amount effective to reduce the symptoms of pain (or analgesia); 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 in the arrangement 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 steps such as electrophoresis, crystallization, using, for example, a chiral HPLC column, in the presence of a resolving agent 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 during chemical reactions or processing where there is no stereoselectivity or stereospecificity.

"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-C_nWhen alkyl, with (phenyl) 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, andbutenyl.

"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.

Halogens are well known in the art, preferably F, Cl, Br, I.

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 ring, a partially unsaturated ring, or an 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 in the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that it is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocycles described herein may be substituted on carbon or nitrogen atoms, as long as the resulting compound is 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, thiazoyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl (benz [ b ] thiophenyl), isoquinolinyl, 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 not 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. Aryl is preferably phenyl, naphthyl, etc.

"depression" includes low mood, decreased activity interest, reduced or irritated mental activity, altered appetite, inattention or delightful and underliness, 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 psychiatric 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 one another.

"salts of compounds" are derivatives of the disclosed compounds wherein the parent compound is modified by making 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 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 such compounds 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, ethane disulfonic, oxalic, isethionic, HOOC- (CH) sulfonic₂)_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 antidepressant effect over 7 days with different doses of drug;

FIG. 2 antidepressant effect of Compounds C and D;

FIG. 3 Compound I6 shows no allelochemical effect;

FIG. 4 Compound C has a behavioral bloom Effect;

FIG. 5 Compound D has a behavioral bloom Effect;

FIG. 6I6 shows no site preference effect on mice;

FIG. 7 Compound C induces positional bias;

figure 8 Compound D induces positional bias.

Detailed Description

Example 1: synthesis of (2R,6R) -6-Hydroxydemethylketamine (HNK)

The method comprises the following steps: adding 50 g of magnesium powder into a two-mouth bottle or a three-mouth bottle, slowly dropwise adding 119.2 g of bromocyclopentane and THF mixed solution after initiation, and refluxing for 2-4h after dropwise adding is finished to prepare 1.6mol/L cyclopentyl format reagent. A mixture of THF and o-chlorobenzonitrile (50.0g) was added 840 mg of CuBr and cyclopentyl format reagent (1.6mol/L, 280ml) was added dropwise under ice bath conditions. And refluxing for 1h after the dropwise addition is finished, cooling to room temperature, adding 100ml of water, then adding 200ml of 15% dilute sulfuric acid solution, stirring overnight, spin-drying THF, extracting with EA, drying, and passing through a silica gel column to obtain 60g of the compound A2-chlorophenyl cyclopentyl ketone with the yield of 80%.

Step two: according to the reported method (Bioorganic & Medicinal Chemistry 2013,12,5098), compound A20 g (96mmol) is dissolved in 400 ml EA, after dissolution, copper bromide (54 g, 242mmol) is added, the mixture is heated under reflux for 3 hours, then cooled to room temperature, solid insoluble substances are filtered by using kieselguhr, and after washing filter residue by adding dichloromethane, the solid insoluble substances are combined with filtrate and concentrated to obtain compound B2-chlorophenyl (1-bromocyclopentyl) ketone as a yellow oily substance. The product was purified by column on silica gel to give 22 g of Compound B in 80% yield.

Step three: ammonia gas was bubbled through 200ml of ammonia until saturation, compound B (10g) was added, stirring was carried out for 24h, compound C precipitated out, filtered and dried to give brown solid compound C (7 g) which was directly subjected to the next step with a yield of 70%.

Step four: compound C (5g) was dissolved in dry THF, HCl gas was bubbled through to a solution pH of 1, and the solution was spun dry to give the hydrochloride salt as a solid. Adding the solid hydrochloride into a single-neck flask, placing the single-neck flask in an oil bath at 190 ℃ under the protection of nitrogen for about 20min, cooling to room temperature, adding a saturated solution of sodium bicarbonate for neutralization, extracting with DCM, and concentrating and crystallizing to obtain 2.9 g of compound D demethylketamine HNK racemate with the yield of 75%.¹H NMR(400MHz,CDCl₃)：δ7.67(dd,J＝7.8,1.5Hz,1H),7.37–7.32(m,2H),7.25(m, 1H),2.78–2.71(m,1H),2.61(m,1H),2.51–2.43(m,1H),2.08–2.0(m,1H),1.88–1.63 (m,4H)。

Step five: dissolving compound D (1.11 g, 5mmol) in 2ml of methanol, adding L-tartaric acid (2.5mmol), stirring for 1h, dropping into 10 ml of acetone, standing until crystallization, and filtering to obtain L-tartrate crystals. The obtained L-tartrate crystals were recrystallized for 3 more times. The crystals were neutralized by adding sodium bicarbonate solution and extracted with EA to give 165 mg of optically pure compound e, (r) -desmethylketamine with an optical purity of 98.3% ee% and a yield of 15% by chiral HPLC.

Chiral HPLC detection step: dissolving 1mg of compound E and 1mg of the racemate compound D of a control in 1ml of ethanol, and performing normal-phase uniformity analysis on an Agilent 1260-A high performance liquid chromatograph, a chromatographic column Chiralcel-AD-H (4.6mm X250 mm), a mobile phase A: (n-hexane + 0.1% diethylamine), mobile phase B: (ethanol + 0.1% diethylamine), a: B ═ 40:60, flow rate 1 mL/min. Compound E: retention time of the R isomer was 6.8min and the corresponding S isomer was 5.3 min.

Step six: compound E (2.23g, 10mmol) was added to 60mL THF, triethylamine (2.7mL, 20mmol) and Boc₂O (3.3g,15mmol), refluxing for 6h, cooling, spin-drying, and passing through a silica gel column gave compound F2.92 g, 90% yield.¹H NMR(400MHz,CDCl₃)：δ7.81(d,J＝8.1Hz,1H),7.40 –7.28(m,2H),7.24–7.12(m,1H),6.57(s,1H),3.82(d,J＝14.4Hz,1H),2.45–2.36 (m,1H),2.28(m,1H),2.04(m,1H),1.89–1.56(m,4H),1.27(s,9H).¹³C NMR(100 MHz,CDCl₃)：δ207.9,152.3,134.5,132.6,130.3,130.0,128.3,125.2,78.0,66.1, 38.5,37.4,29.7,27.2,20.9。

Step seven: adding a compound F (2.91g, 9mmol) into dry 60ml THF, cooling to-78 ℃ under the protection of argon, adding 5ml HMPA, then slowly dropwise adding a 2M THF solution of LDA (12ml, 24mmol), stirring for 30-40min, then slowly heating to-30 ℃ and stirring for 1h, then cooling to-78 ℃ again and adding trimethylchlorosilane TMSCl (2.6g, 24mmol), slowly heating to-50 ℃, stirring for 3h, pouring a saturated ammonium chloride solution and returning to room temperature, concentrating a solvent THF and adding EA for extraction, and adding anhydrous Na into an organic phase₂SO₄Drying, spin-drying the solvent and vacuum drying, dissolving the resulting oil in 100ml of anhydrous DCM, cooling to-15 deg.C under argonAdding mCPBA (2.5g, 11mmol) under protection, stirring for 1h, heating to room temperature, adding 50ml DCM, stirring for 1h, adding saturated sodium thiosulfate and sodium bicarbonate solution (1:1), extracting with DCM, spin-drying the solvent, vacuum-drying, dissolving the obtained oily substance with 100ml THF, cooling to-5 deg.C, adding tetrabutylammonium fluoride (3g, 11.4mmol), stirring for 30min, adding saturated NaHCO₃The solution was extracted with EA, solvent dried and vacuum dried over silica gel column to give compound g1.92g yield 65%.¹H NMR(400MHz,CDCl₃)：δ7.81(d,J＝7.8Hz,1H), 7.34(m,2H),7.24(m,1H),6.60(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),1.68–1.57(m,1H),1.55–1.40 (m,1H),1.30(s,9H).¹³C NMR(100MHz,CDCl₃)：209.8,153.2,134.1,133.6,131.3, 130.8,129.5,126.2,79.3,72.2,66.5,40.3,38.7,28.1,19.4。

Step eight: compound G (680mg) was dissolved in 5mL of dry THF, saturated with gaseous HCl at room temperature and stirred for 4H, 20mL of dry ether was added and crystals precipitated, and filtered to give 520mg of compound H (2R,6R) -6-Hydroxydesmethylketamine (HNK) hydrochloride in 95% yield.¹H NMR(400MHz, CD₃OD)：δ7.85(m,1H),7.65–7.51(m,3H),4.28(m,1H),3.19(m,1H),2.30(m,1H), 1.81–1.72(m,2H),1.64–1.51(m,2H)。

Example 2: synthesis of Compound I6

Dissolving the compound G (170mg, 0.5mmol) in 3mL of dry THF, adding dry triethylamine (0.28mL, 2mmol), adding 3-furoyl chloride (130mg,1mmol) under ice bath condition, slowly raising to room temperature within 1 hour, stirring overnight, adding sodium bicarbonate solution, EA extracting, spin drying solvent and vacuum drying, passing through silica gel column to obtain compound H₆173mg of N-Boc- (2R,6R) -6- (3-furan) formyloxy-desmethylketamine was obtained at 80% yield.¹H NMR(400MHz,CDCl₃)：8.11(br,1H),7.81-7.79(brs, 1H),7.42-7.28(m,4H),6.67(brs,1H),6.63(m,1H),5.35-5.31(m,1H),3.92-3.87 (m,1H),2.39-2.33(m,1H),1.94-1.74(m,4H),1.30(brs,9H).¹³C NMR(100MHz, CDCl₃)：202.5，168.5，161.4，153.3，148.4，143.8，134.3，133.7，131.4，131.1， 129.8，126.3，118.5，109.1,79.4，73.5，67.2，38.5，35.8，28.2，19.8.

Compound H₆(170mg) in 3mL of dry THF, saturated with gaseous HCl at room temperature and stirred for 4h, 15-20mL of dry ether are added and crystals precipitate, which are filtered off in vacuo to give Compound I₆(2R,6R) -6- (3-Furan) formyloxy desmethylketamine hydrochloride 124mg, 86% yield.¹H NMR(400MHz, CD₃OD)：9.02(brs,3H)，8.09(s,1H)，7.79(s,1H)，7.43-7.40(m,4H)，6.75 (br,1H)，5.39(m,1H)，3.76-3.54(m,1H)，2.41-2.32(m,2H),2.10-1.93(m, 3H)¹³C NMR(100MHz,CD3OD)：δ200.2，168.5，161.3，148.8，144.0，136.9， 134.8，132.1，131.5，129.3，128.4，118.5，110.0，73.6，68.2，37.3，3 5.1， 19.5.

Example 3: synthesis of Compounds C and D

Compounds C and D were prepared by the following preparation methods.

Example 4: and (3) activity test:

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 light conditions and monitored by a digital camera. During the test, the mice were placed individually in clear glass cylinders (28.5 cm high, 14 cm diameter) filled with 20 cm water (23. + -. 1 ℃). On the first day, mice were trained for 6 minutes and then removed from the cylinders. The next day, mice were given saline, HNK, I6, C, D and tested for time incomprehensible at various time intervals. During the last 4 minutes of the entire 6 minute swimming test, the resting time, defined as passive flotation, was recorded by EthoVision XT (Noldus, the netherlands) by the Noldus system, with no movement other than the action necessary to keep the animal's head on water. After every two to three trials, the water in the bottle was replaced. After the swimming test, the mice were removed from the water and dried under an infrared lamp.

Mice were gavaged with 1mg (a), 10mg (b) and 30mg (c) of HNK, I6 and their immobility time was measured after 1 hour and 7 days, respectively. The percentage of immobility time is expressed as mean ± SEM. P <0.05, p <0.01, compared to the base test. Each group N is 8. salene, saline group; i6, I6 treatment group; HNK: 2R, 6R-hydroxynorketoamine treated group.

2. Study of addiction

Materials and methods animals male mice C57BL/6J were randomly grouped at 8-12 weeks, 10 mice per group, body weight 18-22 g, room temperature (22 + -1 deg.C), humidity (50 + -10)%, illumination time 8: 00-20: 00, the mice freely eat drinking water and adapt to the experiment environment for at least 2-3 days before the experiment. All experiments are carried out at 8: 00-16: 00.

Behavior sensitization experiment:

1.1 autonomous activity determination of small animals, namely an infrared analysis system for spontaneous activity of animals, which consists of a spontaneous activity box, an infrared probe device and a data acquisition system. The size of the spontaneous activity box is 40cmX 40cm X65 cm, and the box has sound insulation and light insulation and ventilation devices. And recording the animal activity condition by an infrared probe, and calculating the spontaneous activity times of the animal. To test the effect of the drug on the spontaneous activity of the mice, the mice were randomized into 4 groups of 10 mice each. The components are as follows: vehicle, I6, C, D (5.0, 10.0, 30.0mg/kg), mor (10 mg/kg). Respectively performing intragastric administration for 1 time every morning for 7 days; thereafter, drug was stopped for 7d (without any treatment). On day 15, each group of mice was gavaged with Veh, drug (5.0, 10.0, 30.0mg/kg) challenge. Spontaneous activity of mice was measured within 1h immediately after d1, d7, d15 administration.

1.2 CPP experiment: the three-chamber CPP system comprises left and right black and white boxes (25cmx25cmx30cm) separated by a middle box (10cmx25cmx30cm), and the mice are placed in the middle box during the experiment and can freely shuttle to the black box and the white box. One shuttle gate is arranged between the black box and the white box and the middle box respectively, and the size of the shuttle gate is 5cmx5 cm. The experiment adopts a bias program, which is divided into 3 stages of pre-testing, training and testing, and the consistency of environmental conditions such as light, color tone, smell and the like in the box is ensured in the whole experiment process.

Pre-testing: d1-3, the compartment internal partition was opened, all mice were placed in the intermediate compartment after subcutaneous injection of saline, and allowed to move freely in the compartment for 15min, 1 time per day, for 3 consecutive days. Recording the residence time of the mouse in a black and white box respectively, and determining the natural preference tendency of the mouse; the non-natural preference box is used as a medicine accompanying box to train the mouse.

A training period: d4-9, closing shuttle gate, randomly grouping mice including Veh, mor, I6, C, D (5.0, 10.0, 30.0mg/kg), mor (10mg/kg), 10 per group. In the morning, all mice are first filled with stomach and given with normal saline, and immediately placed in a non-accompanied medicine box (black box) for 45 min; in the afternoon, the individual animals were gavaged with Veh, mor, I6, C, D (5.0, 10.0, 30.0mg/kg) and immediately placed in a companion box (white box) for 45 min. The training sequence for the double days is reversed. The interval between the morning training and the afternoon training is more than 6h, the training time of each day is fixed, the training is continuously carried out for 6d, and 10 training devices are arranged in each group.

And (3) testing period: d10 remove the partition and place the mouse in the middle box and let it run freely while recording the residence time of the mouse in the white box within 15 min.

Statistical analysis: experimental data are presented as X ± SEM. Statistical analysis is carried out by adopting graphpad software, and t test is adopted for comparing two groups; the one-way ANOVA analysis was used for the comparisons between groups, followed by two-by-two comparison using the LSD method.

3. Location preference test

Positional preferences were tested by a three-compartment system, mice were trained using a kit of unnatural preferences, and during the training period mice were given physiological saline (Veh), morphine (mor, 10mg/kg), I6, C and D (5.0, 10.0, 30.0mg/kg), respectively, and tested after 6 days of continuous training, and the residence time of the mice in the white box was recorded for 15 min. P <0.05(n ═ 10) compared to the Veh group.

Example 5: results of the experiment

1. Results of mouse depression-like behavior test:

1mgHNK and I6 have no antidepressant effect; 10mgHNK and I6 have antidepressant effect, I6 has long-acting effect, the drug effect is not attenuated basically in 7 days, the drug effect is attenuated quickly in 7 days of HNK, and the drug effect is not attenuated basically in 7 days. 30mgHNK and I6 have antidepressant effect, I6 has long-acting effect, the drug effect is not attenuated basically in 7 days, the drug effect is attenuated quickly in 7 days of HNK, and the drug effect is not attenuated basically in 7 days.

Compounds C and D had no antidepressant effect at 30 mg.

The I6-treated group still had a significant antidepressant effect 7 days after administration, as evidenced by a reduction in the immobility time of the animals in forced swimming, compared to the HNK-treated group. The I6 group had less immobility time. There was no significant difference between the 10mg and 30mg treatment groups, although the 30mg group exhibited a stronger trend of decrease. Neither compound C, D had antidepressant effect.

2. Experiment on addiction

Different doses (5mg, 10mg, 30mg) of I6 did not exert a fujihua effect on mice.

Different doses (5mg, 10mg, 30mg) of C and D had a bloom-inducing effect in mice.

3. Location preference test

Different doses (5mg, 10mg, 30mg) of I6 had no site-preference effect on mice.

Different doses (5mg, 10mg, 30mg) of C and D induced positional preference in mice.

The technical features of the above embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the above embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the scope of the present description should be considered as being described in the present specification.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The application of a compound and a salt thereof in preparing a medicament for preventing or treating depression and improving anxiety is disclosed, wherein the compound has the structure:

2. use according to claim 1, characterized in that: the structure of the compound is as follows:

3. the use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier.

4. The use of claim 2, wherein the medicament further comprises a pharmaceutically acceptable carrier.

5. The use as claimed in any one of claims 1 to 4, wherein the anti-depression disorder comprises: bipolar depression and major depressive disorder.