WO2022041175A1

WO2022041175A1 - Use of long-acting and low-addiction hnk derivative for preparing medicament

Info

Publication number: WO2022041175A1
Application number: PCT/CN2020/112376
Authority: WO
Inventors: 李书鹏; 周强
Original assignee: 深圳瑞健生物科技有限公司
Priority date: 2020-08-31
Filing date: 2020-08-31
Publication date: 2022-03-03

Abstract

The present application relates to use of a compound for preparing a medicament for anti-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 present application has a longer drug effect time, and the compound of the present application is basically not addictive.

Description

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

technical field

The present application relates to the field of medicine, in particular to the application of a low-addiction HNK derivative in the treatment or prevention of depression, including complex regional pain syndrome (CRPS) and other diseases.

Background technique

Ketamine is a representative of phencyclidine intravenous anesthetics commonly used in clinical practice, and is one of the anesthetics developed rapidly in clinical and basic research in recent years. In clinical practice, it is often used to meet the needs of anesthesia in pediatrics, obstetrics, perioperative period and patients with special diseases because of its rapid induction, short action time, quick recovery, and less impact on the respiratory and circulatory systems.

Ketamine was first synthesized in 1962, used in humans in 1965, and officially approved by the FDA for clinical use in 1970. Its typical "dissociative anesthesia" and short-acting precise analgesia made it a smash hit, but the subsequent discovery of psychiatric side effects and the rapid development of other intravenous anesthetics greatly reduced the clinical use of ketamine. In the past 10 years, with the study of ketamine usage and dosage, and its anti-inflammatory, antidepressant, neuroprotective, analgesic and other effects have been discovered, the medical community's interest in ketamine has revived.

For a long time, ketamine has strong analgesia, amnesia, and can preserve spontaneous breathing and airway protective reflex, and maintain hemodynamic stability, so that the role of ketamine in prehospital anesthesia and analgesia cannot be ignored. Ketamine has both neurotoxic and neuroprotective effects.

Ketamine has effects on postoperative cognitive function. Some researchers tested 50 children who received ketamine anesthesia and found that ketamine general anesthesia could reduce the cognitive function of children 6 hours after operation, but had no effect on cognitive function at 24 hours after operation. Hudetz et al found that administration of 0.5 mg/kg ketamine during induction of general anesthesia could reduce the incidence of postoperative cognitive impairment 1 week after cardiac surgery. In recent years, numerous clinical trials have confirmed that a single small dose of ketamine can reduce the incidence of postoperative cognitive dysfunction after surgery.

Ketamine has analgesic properties. Sub-anesthetic doses of ketamine are often used for anti-hyperalgesia, and the treatment of acute and chronic pain. Studies have shown that gargling with ketamine-saline mixture before induction of anesthesia can significantly reduce the incidence and severity of postoperative sore throat caused by tracheal intubation under general anesthesia. Intraoperative opioid use increases postoperative opioid analgesic doses, an effect called opioid tolerance. It is clinically found that the use of ketamine can prevent opioid tolerance, reverse morphine tolerance, and enhance the analgesic effect of morphine. Some studies have also confirmed that intraoperative application of low-dose ketamine can prevent remifentanil-induced postoperative hyperalgesia. Cagla et al. found that 0.15 mg/kg of ketamine was administered intravenously to patients undergoing knee arthroscopy and found that ketamine could significantly improve postoperative analgesia satisfaction, and the sedation score was lower than that of the ketamine combined with midazolam group.

Ketamine has lung protective effects. In recent years, ketamine has been found to have significant lung protective effects. Clinical experiments have confirmed that both intravenous and nebulization before single-lung ventilation in thoracic surgery can reduce the level of inflammatory factors in the blood, while nebulization inhalation is more beneficial to the cardiovascular system and airway pressure, and nebulization on the side of lung ventilation has the effect. Better than double lung nebulization. Ketamine is also commonly used clinically in the rescue of fatal asthma attacks when conventional treatment fails, and its use is recognized to improve prognosis.

Ketamine has antidepressant properties. In 2000, Berman et al reported for the first time that more than 50% of patients within 72 hours after a single intravenous injection of sub-anesthetic dose of ketamine (0.5 mg/kg) had a reduction of more than 50% in the Hamilton Depression Scale score. 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.

The application number is CN 201280062294X, and the invention name is (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydrogenation and hydroxylated metabolites of (R,S)-ketamine in Patent application for use in the treatment of depression and neuropathic pain, disclosing that CNS (central nervous system) side effects are related to the activity of (R,S)-ketamine at NMDA receptors, based on ketamine, research and Synthesized (2R,6R;2S,6S)-Hydroxynorketamine (HNK), which is inactive at NMDA receptors, thus avoiding possible side effects, and is said to have therapeutic properties for bipolar depression, major depressive disorder , Alzheimer's dementia, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, or neuropathic pain.

In our experimental study, we found that (2R,6R;2S,6S)-hydroxynorketamine (HNK) did not last long after administration, and basically had no activity within 1 week, which seriously limited the treatment Desired long-lasting effect in depression. At the same time, our research also found that the application of HNK will produce a certain degree of addiction, which will cause adverse effects on the patient's body and mind. Therefore, how to modify the structure of (2R,6R;2S,6S)-hydroxynorketamine (HNK) to obtain a drug with longer efficacy and lower addiction will have great therapeutic potential.

SUMMARY OF THE INVENTION

This application relates to an antidepressant, improving anxiety and post-traumatic stress syndrome, anesthesia, analgesia, improving cognitive function, lung protection, prevention or treatment of amyotrophic lateral sclerosis or prevention or treatment of complex regional pain syndrome symptomatic compounds.

Compared with the existing known HNK compounds, the compound of the present application has a longer efficacy time, which is specifically manifested in that HNK is metabolized within a week and has no activity, while the drug effect time of the compound of the present application can last for more than 1 week, Specifically, it is more than 7 days, more than 10 days, more than 14 days, and the like. Moreover, the compounds of the present application do not substantially produce addictive properties, and their addictive properties are 2 times, 5 times, 10 times, or 20 times lower than that of HNK compounds.

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

in:

Where m is an integer from 0 to 3, and n is an integer from 0 to 4;

R ₁ and R ₂ are each independently selected from H, halogen, hydroxy, amino, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C 1 -C 6 alkenyl Substituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocyclyl, substituted or unsubstituted C ₁ -C ₆ alkoxy One or more of substituted or unsubstituted mono- and di-C ₁ -C ₆ alkylamino groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;

R ₃ is halogen;

R ₄ is selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₈ acyl, substituted or unsubstituted aryl acyl or substituted or unsubstituted heteroaryl acyl;

R ₅ is selected from substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ₆ is selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C 2 -C 6 alkynyl C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₈ acyl, substituted or unsubstituted arylacyl or substituted or unsubstituted heteroarylacyl;

_The substitution means by OH; NH ₂ ; C ₁ -C ₁₀ alkyl, alkenyl or alkynyl _; C ₁ -C ₁₀ alkylamino _; ₂₀ alkoxy; C ₁ -C ₁₀ carbonyl; C ₃ -C ₁₀ cycloalkyl; 3-10-membered heterocyclic group with one or more heteroatoms selected from N, S, O, P; C ₆ -C _20aryl ; C2 _- _{C20heteroaryl} ; nitrocyano, or halogen substituted.

Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula II:

Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula III:

where p is an integer from 0 to 3.

Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula IV:

where p is an integer from 0 to 3.

Preferably, the above-mentioned compound is characterized in that it is the following compound:

The application also provides a compound, a salt of the compound, a stereoisomer, or a tautomer, and its structural formula is as follows:

wherein R ₇ is H or a protecting group.

Preferably, the above-mentioned compound, compound salt, stereoisomer or tautomer is characterized by the following structure:

or

The present application also provides a pharmaceutical composition, characterized by comprising the compound, salt, stereoisomer, or tautomer of any one of claims 1-8, and optionally a pharmaceutical composition an acceptable carrier.

The application also provides a preparation method of a compound, characterized in that:

Any compound as described above is used in the preparation of anesthesia, analgesia, improving cognitive function, lung protection, antidepressant, improving anxiety and post-traumatic stress syndrome, amyotrophic lateral sclerosis, complex regional pain syndrome medicament applications in .

Wherein the pain includes: chronic pain or neuropathic pain; depression includes: bipolar depression, major depressive disorder; improvement of anxiety and post-traumatic stress syndrome; improvement of cognitive function includes prevention or treatment of Alzheimer's dementia, Parkinson et al.

All of the above diseases also cover preventive or therapeutic effects.

Stereoisomers of all the above compounds include enantiomers and diastereomers.

All of the compounds described above are not limited to any one particular tautomeric form, but include all tautomeric forms, insofar as the compounds exist in different tautomeric forms.

All compounds described above include compounds having all possible isotopes of the atoms present 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 application also provides a pharmaceutical composition, and the compounds disclosed herein can be administered as neat chemicals, but are preferably administered as pharmaceutical compositions. Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain the compound or salt as the only active agent, but preferably contains at least one other active agent. In certain embodiments, the pharmaceutical composition comprises about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of a compound of formula I and optionally about 0.1 mg to about 2000 mg in a unit dosage form , an oral dosage form of about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the other active agent.

The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, bucally, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers to give. The pharmaceutical compositions can 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 make them suitable for administration to the patient to be treated. The carrier may be inert or it may itself possess pharmaceutical benefits.

Types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents agents, and wetting agents. Some carriers may be listed in more than one category, eg, vegetable oils may 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. Optional active agents can be included in pharmaceutical compositions that do not substantially affect the activity of the compounds of the present application.

A compound or salt 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 can be administered in conjunction with another active agent selected from any of the following:

Antidepressants : escitalopram oxalate, filoctine, paroxetine, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, milt Zapine, venlafaxine, atomoxetine, bupropion, doxepin, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, clozapine Pine, Kexepin, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Carboxamide, Gabapentin, Lamotrigine, Phenytoin, Pregabalin, Donepezil, Galantamine, Memantine, Rivastigmine, tramiprosate, or a pharmaceutically active salt or prodrug thereof, or a combination thereof;

Schizophrenia drugs : aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine, olanzapine, clozapine, Flupentioxol, Perphenazine, Haloperidol, Chlorpromazine, Fluphenazine, Fluphenazine, Paliperidone;

Alzheimer's dementia drugs: donepezil, rivastigmine, galantamine, memantine;

ALS drugs : riluzole;

Pain Medications : Acetaminophen, Aspirin, NSAIDS including: Diclofenac, Diflufenac, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indene, Ketoprofen , ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, Tolmetinopiods, Cox -2 inhibitors such as celecoxib, and narcotic pain medications such as: buprenorphine, butorphanol, codeine, dihydrocodeinone, hydromorphone, oxymethylene levorphan, meperidine , methadone, morphine, nalbuphine, oxycodone, oxymorphone, analgesic new, 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 can be administered in combination with compounds of formula I. Although in some embodiments the other active agent will be administered at doses less than generally prescribed and in some cases less than the minimum approved dose, the other active agent may be administered in accordance with its approved prescribed information.

The present application includes methods of treating depression, particularly bipolar depression and major depressive disorder, particularly treatment-resistant depression, wherein the effective amount of the compound is an amount effective to reduce depressive symptoms , where the reduction in depressive symptoms is a reduction of 50% or greater of the symptoms identified on the Depressive Symptom Rating Scale, or a score of less than or equal to 7 on HRSD ₁₇ , or less than or equal to 7 on QID-SR ₁₆ Equal to 5, or less than or equal to 10 on MADRS.

The present application provides an amount effective to reduce pain (or analgesia) symptoms; wherein the reduction in pain symptoms is a 50% or greater reduction in pain symptoms on a pain rating scale.

Terminology convention:

"Stereoisomers" are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.

"Diastereomers" 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 properties and reactivity. Mixtures of diastereomers can be separated under high resolution analytical steps such as electrophoresis, crystallization, in the presence of resolving agents or chromatography, using eg chiral HPLC columns.

"Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur during chemical reactions or processing without already having stereoselectivity or stereospecificity.

"Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the specified number of carbon atoms, typically 1 to about 12 carbon atoms. The term _C1 - _C6 alkyl as used herein denotes an alkyl group having 1 to about 6 carbon atoms. When C ₀ -C _n alkyl is used herein in conjunction with another group, taking (phenyl)C ₀ -C ₄ alkyl as an example, the designated group, in which case phenyl is formed by a single co- The valence bond (C ₀ ) is bonded directly or 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.

"Alkenyl" refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. The alkenyl groups described herein generally 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 _- _C6 , and C2 _- C4alkenyl. Examples of alkenyl groups include vinyl, propenyl, and butenyl.

"Alkoxy" refers to an alkyl group as defined above having the indicated number of carbon atoms attached through 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, F, Cl, Br, I are preferred.

The term "heterocycle" means a 5- to 8-membered saturated, partially unsaturated, or aromatic ring containing 1 to about 4 heteroatoms selected from N, O, and S and the remaining ring atoms being carbon, or is a 7- to 11-membered saturated, partially unsaturated, or aromatic heterocyclic ring system and a 10- to 15-membered tricyclic ring system containing at least 1 heteroatom selected from a polycyclic ring system of N, O, and S And up to about 4 heteroatoms independently selected from N, O and S are contained in each ring in the polycyclic ring system. Unless otherwise specified, a heterocycle 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 heterocycles described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable. Nitrogen atoms in the heterocycle can 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 heterocyclyl groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetra azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, 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.

"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 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 greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not greater than one. Nitrogen atoms in the heterocycle 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 fusing with a 5- to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, [1,3]dioxin Azolo[4,5-c]pyridyl. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , and 5,6,7,8-tetrahydroisoquinoline. The aryl group is preferably phenyl, naphthyl and the like.

"Depression" includes low mood, decreased interest in activities, decreased mental activity or irritability, changes in appetite, inattention or indecision, excessive guilt or low self-esteem, and is associated with depression, bipolar depression, and depression due to other diseases or conditions. Suicidal ideation may occur in the context of mood disorders, substance-induced mood disorders, and other mood disorders of unknown etiology, and may also be associated with a variety of other psychiatric disorders (including but not limited to psychotic disorders, cognitive impairment, eating disorders, anxiety Symptoms and Personality Disorders) coexist. Longitudinal course, medical history, type of symptoms, and etiology help to distinguish the various forms of affective illness 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 these compounds and pharmaceutically acceptable solvates, including hydrates, of these 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, and include one or more A combination of the above salts. Pharmaceutically acceptable salts include nontoxic and quaternary ammonium salts such as the parent compounds formed from nontoxic inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, etc.; other acceptable inorganic salts include metal salts such as sodium, potassium, Cesium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc., and combinations comprising one or more of the foregoing salts.

Organic salts of compounds include 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, pamoic 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, methanesulfonic acid Salts prepared from organic acids such as sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH ₂ ) _n -COOH (wherein n is 0 to 4), etc.; organic amine salts such as triethylamine salts, pyridinium salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.; and amino acid salts, such as: arginine salts, aspartame Acid salts, glutamate salts, and the like, and combinations comprising one or more of the foregoing salts.

Description of drawings

Figure 1 Antidepressant effect of different doses of drugs within 7 days;

Figure 2 Antidepressant effects of compounds C and D;

Figure 3 Compound I6 has no sensitizer effect;

Figure 4 Compound C has the effect of acting as Minhua;

Figure 5 Compound D has the effect of acting as Minhua;

Figure 6 I6 has no place preference effect on mice;

Figure 7 Compound C induces place preference;

Figure 8 Compound D induces place preference.

detailed description

Example 1: Synthesis of (2R,6R)-6-hydroxydemethylketamine (HNK)

Step 1: In a two-necked bottle or a three-necked bottle, add 50 grams of magnesium powder, slowly add 119.2 grams of bromocyclopentane and THF mixed solution dropwise after initiation, and reflux for 2-4h to obtain 1.6mol/L. Cyclopentyl Grignard reagent. 840 mg of CuBr was added to the mixture of THF and o-chlorobenzonitrile (50.0 g), and cyclopentyl Grignard reagent (1.6 mol/L, 280 ml) was added dropwise under ice bath conditions. After the dropwise addition, refluxed for 1 h, cooled to room temperature, added 100 ml of water, then added 200 ml of 15% dilute sulfuric acid solution, stirred overnight, spin-dried THF, extracted with EA, dried, and passed through a silica gel column to obtain compound A 2-chlorophenyl ring Amyl ketone 60g, yield 80%.

Step 2: According to the reported method (Bioorganic & Medicinal Chemistry 2013, 12, 5098), 20 grams (96 mmol) of compound A were dissolved in 400 milliliters of EA, and after dissolving, copper bromide (54 grams, 242 mmol) was added, and the temperature was refluxed. 3 hours, then cooled to room temperature, the solid insolubles were filtered with celite, the filter residue was washed with dichloromethane, combined with the filtrate and concentrated to obtain a yellow oily compound B 2-Chlorophenyl(1-bromocyclopentyl)methane ketone. After passing through a silica gel column, 22 g of pure compound B was obtained with a yield of 80%.

Step 3: Pass ammonia gas into 200ml of ammonia water until saturation, add compound B (10g), stir for 24h, compound C is precipitated, filtered, and dried to obtain brown solid compound C (7g) and proceed directly to the next step, with a yield of 70 %.

Step 4: Dissolve compound C (5 g) in dry THF, pass HCl gas until the pH of the solution is 1, and spin the solution to obtain solid hydrochloride. The solid hydrochloride was added to a single-necked flask, placed in an oil bath at 190°C under nitrogen protection, cooled to room temperature for about 20 minutes, neutralized by adding saturated sodium bicarbonate solution, extracted with DCM, concentrated and crystallized to obtain compound D normethyl 2.9 g of ketamine HNK racemate, 75% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (dd, J=7.8, 1.5 Hz, 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 5: Dissolve compound D (1.11 g, 5 mmol) in 2 mL of methanol, add L-tartaric acid (2.5 mmol), stir for 1 h, drop into 10 mL of acetone, stand for crystallization, and filter to obtain L-tartrate crystals. The obtained L-tartrate crystals were continuously recrystallized for 3 times. The crystals were neutralized by adding sodium bicarbonate solution and extracted with EA to obtain 165 mg of optically pure compound E(R)-desmethylketamine. The optical purity detected by chiral HPLC was 98.3%ee%, and the yield was 15%.

Chiral HPLC detection steps: Dissolve 1 mg each of compound E and control racemate compound D in 1 ml of ethanol, and place them on an Agilent 1260-A high performance liquid chromatograph for normal phase uniformity analysis. The chromatographic column Chiralcel- AD-H (4.6mm X 250mm), mobile phase A: (n-hexane+0.1% diethylamine), mobile phase B: (ethanol+0.1% diethylamine), A:B=40:60, flow rate 1mL/ min. Compound E: the retention time of the isomer of R configuration is 6.8 min, and the retention time of the corresponding isomer of S configuration is 5.3 min.

Step 6: Compound E (2.23 g, 10 mmol) was added to 60 ml of THF, triethylamine (2.7 mL, 20 mmol) and Boc ₂ O (3.3 g, 15 mmol) were added, refluxed for 6 h, cooled, spin-dried, and passed through a silica gel column to obtain Compound F 2.92 g, 90% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (d, J=8.1 Hz, 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). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 207.9, 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 7: Compound F (2.91g, 9mmol) was added to dry 60ml THF, cooled to -78°C under argon protection, 5ml HMPA was added, and then 2M LDA in THF solution (12ml) was slowly added dropwise. , 24mmol), stirred for 30-40min, then slowly heated to -30°C and stirred for 1h, then cooled to -78°C and added trimethylchlorosilane TMSCl (2.6g, 24mmol), slowly heated to -50°C, stirred for 3h , poured into saturated ammonium chloride solution and returned to room temperature, concentrated the solvent THF and added EA for extraction, the organic phase was dried by adding anhydrous Na ₂ SO ₄ , the solvent was spin-dried and vacuum-dried, the obtained oil was dissolved in 100 ml of anhydrous DCM , cooled to -15°C, under argon protection, mCPBA (2.5 g, 11 mmol) was added, stirred for 1 h, then warmed to room temperature, added 50 ml of DCM and stirred for 1 h, then poured into saturated sodium thiosulfate and sodium bicarbonate solution ( 1:1), extract with DCM, spin dry the solvent and vacuum dry, add 100ml of THF to the obtained oil to dissolve, then cool to -5°C, add tetrabutylammonium fluoride (3g, 11.4mmol), stir for 30min, add Saturated NaHCO ₃ solution, extracted with EA, spin-dried the solvent and dried in vacuo, passed through a silica gel column to give compound G 1.92 g in 65% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (d, J=7.8 Hz, 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). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 8: Dissolve compound G (680 mg) in 5 mL of dry THF, pass gaseous HCl to saturation at room temperature and stir for 4 h, add 20 mL of dry ether, crystals are precipitated, and filter to obtain compound H(2R,6R)-6- Hydroxy desmethylketamine (HNK) hydrochloride 520 mg, 95% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.85 (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 16

Compound G (170 mg, 0.5 mmol) was dissolved in 3 mL of dry THF, dry triethylamine (0.28 mL, 2 mmol) was added, then 3-furoyl chloride (130 mg, 1 mmol) was added in an ice bath, and then over 1 hour Slowly rise to room temperature, stir overnight, then add sodium bicarbonate solution, extract with EA, spin dry the solvent and dry in vacuo, pass through a silica gel column to obtain compound H ₆ N-Boc-(2R,6R)-6-(3-furan ) formyloxydesmethylketamine 173 mg, 80% yield. ¹ H NMR (400 MHz, CDCl ₃ ): 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). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 H ₆ (170 mg) was dissolved in 3 mL of dry THF, gaseous HCl was passed through to saturation at room temperature and stirred for 4 h, 15-20 mL of dry ether was added, crystals were precipitated, and vacuum filtration was used to obtain compound I ₆ (2R, 6R)- 6-(3-Furan)formyloxydesmethylketamine hydrochloride 124 mg, 86% yield. ¹ H NMR (400 MHz, CD ₃ OD): 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) ¹³ C NMR (100MHz, CD3OD): δ 200.2, 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, 35.1, 19.5.

Example 3: Synthesis of Compounds C and D

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

Example 4: Activity test:

1. Forced swimming experiment

Mice were transferred to the laboratory 1 hour before the forced swim test (FST). The test was conducted under normal light conditions and monitored by digital cameras. During the test, the mice were individually placed in transparent glass cylinders (28.5 cm in height, 14 cm in diameter) filled with 20 cm of water (23±1°C). On the first day, mice were trained for 6 minutes and then removed from the cylinder. On the second day, mice were tested for time comprehension after different time intervals after administration of saline, HNK, I6, C, D. Immobility time, defined as passive floatation, was recorded through the EthoVision XT of the Noldus system (Noldus, The Netherlands) during the last 4 minutes of the entire 6-minute swim test, except for any movements necessary to keep the animal's head on the water Besides, there is no other movement. After every two to three trials, change the water in the bottle. After the swim test, the mice were removed from the water and dried under infrared light.

Mice were given 1 mg (A), 10 mg (B) and 30 mg (C) of HNK, I6 by gavage, respectively, and their immobility time was measured after 1 hour and 7 days. The percentage of immobility time is expressed as mean ± SEM. *p<0.05, **p<0.01, compared to base test. N=8 per group. saline, saline group; I6, I6 treatment group; HNK: 2R, 6R-hydroxynorketamine treatment group.

2. Addiction Research

Materials and Method

Animals: 8-12 week old C57BL/6J male mice were randomly divided into groups, 10 mice in each group, weighing 18-22 g, housed at room temperature (22±1℃), humidity (50±10)%, light time 8:00-20 : 00, the mice had free access to food and water, and adapted to the experimental environment for at least 2-3 days before the experiment. All experiments were performed from 8:00 to 16:00.

Behavioral Sensitization Experiment:

1.1 Determination of autonomous activity of small animals: The infrared analysis system of animal spontaneous activity is composed of a spontaneous activity box, an infrared probe device and a data acquisition system. The size of the spontaneous activity box is 40cmX40cmX65cm, with sound insulation and light insulation, and a ventilation device. The activity status of the animals was recorded by the infrared probe, and the number of spontaneous activities of the animals was calculated. To test the effect of the drug on the spontaneous activity of mice, the mice were randomly divided into 4 groups with 10 mice in each group. Grouping: vehicle, I6, C, D (5.0, 10.0, 30.0 mg/kg), mor (10 mg/kg). The patients were given intragastrically once a day in the morning for 7 consecutive days; after that, the drug was stopped for 7 days (without any treatment). On the 15th day, mice in each group were challenged with Veh and drugs (5.0, 10.0, 30.0 mg/kg) by gavage. Immediately after administration on d1, d7, and d15, the spontaneous activity of mice was measured within 1 h.

1.2 CPP experiment: The three-chamber CPP system includes left and right black and white boxes (25cmx25cmx30cm) separated by the middle box (10cmx25cmx30cm). During the experiment, mice are put in from the middle box and can freely shuttle to the black and white boxes. There is a shuttle door between the black and white boxes and the middle box, the size is 5cmx5cm. The experiment adopts a biased procedure, which is divided into three stages: pre-testing, training, and testing. During the whole experiment, the environmental conditions such as light, color, and smell in the box are guaranteed to be consistent.

Pre-test: On days 1-3, the partitions in the box were opened, and all mice were subcutaneously injected with saline and placed in the middle box, allowing them to move freely in the box for 15 minutes, once a day for 3 consecutive days. The residence time of the mice in the black and white boxes was recorded to determine the natural preference of the mice; the mice were trained with the non-natural preference box as the companion medicine box.

Training period: d4-9, the shuttle gate was closed, and the mice were randomly divided into groups, including Veh, mor, I6, C, D (5.0, 10.0, 30.0 mg/kg), mor (10 mg/kg), 10 mice in each group. On odd-numbered days, all mice were given normal saline by gavage first in the morning, and immediately placed in the non-medicated box (black box) for 45 minutes; on odd-numbered days, the mice were given Veh, mor, I6, C, D (5.0, 10.0, 30.0 mg/gavage) respectively in the afternoon on odd-numbered days. kg), and then immediately put it into the companion medicine box (white box) for 45 min. The training sequence for even-numbered days is reversed. The training interval in the morning and afternoon was greater than 6h, and the training time was fixed every day.

Test period: on d10, remove the partition, put the mice in the middle box, let them run freely, and record the time that the mice stay in the white box within 15 minutes.

Statistical analysis: Experimental data are expressed as X±SEM. Graphpad software was used for statistical analysis, and t-test was used for comparison between two groups; one-way ANOVA was used for comparison between multiple groups, and then LSD method was used for pairwise comparison.

3. Positional Preference Experiment

Positional preference was tested by a three-chamber system. Mice were trained with a non-natural preference box as a companion medicine box. During the training period, the mice were given saline (Veh), morphine (mor, 10 mg/kg), I6, C and D (5.0, 10.0, 30.0 mg/kg), test after 6 days of continuous training, and record the stay time of mice in the white box within 15 min. *P<0.05 (n=10) compared to Veh group.

Example 5: Experimental Results

1. Test results of depressive-like behavior in mice:

1mgHNK, I6 have no antidepressant effect; 10mgHNK, I6 have antidepressant effect, I6 has a long-acting effect, the effect is basically not attenuated within 7 days, and the effect of HNK is attenuated quickly within 7 days, and basically no effect on the 7th day. 30mg HNK and I6 have antidepressant effects, I6 has a long-acting effect, and the effect is basically not attenuated within 7 days, while the effect of HNK decays rapidly within 7 days, and there is basically no effect on the 7th day.

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

Compared with the HNK-treated group, the I6-treated group still had a significant antidepressant effect 7 days after dosing, as manifested by a reduction in the animals' immobility time during forced swimming. The I6 group had less immobility time. There was no significant difference between the 10 mg and 30 mg treatment groups, although the 30 mg group showed a stronger decreasing trend. Compounds C and D had no antidepressant effect.

2. Addiction Experiment

Different doses (5mg, 10mg, 30mg) of I6 had no effect on the behavior of mice.

Different doses (5mg, 10mg, 30mg) of C and D have behavioral Minhua effect on mice.

3. Positional Preference Experiment

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

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

The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

The above-mentioned embodiments only represent several embodiments of the present application, and the descriptions thereof are relatively specific and detailed, but should not be construed as limiting the scope of the patent application. It should be noted that, for those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the protection scope of the present application. Therefore, the scope of protection of the patent of the present application shall be subject to the appended claims.

Claims

A compound, a salt of a compound, a stereoisomer, or a tautomer in the preparation of a prophylactic or therapeutic anesthesia, analgesia, improved cognitive function, lung protection, antidepressant, improved anxiety and post-traumatic stress syndrome, Use in amyotrophic lateral sclerosis or complex regional pain syndrome medicine, the compound has the structure shown in formula I:

in:

Where m is an integer from 0 to 3, and n is an integer from 0 to 4;

R 1 and R 2 are each independently selected from H, halogen, hydroxy, amino, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 alkenyl Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocyclyl, substituted or unsubstituted C 1 -C 6 alkoxy One or more of substituted or unsubstituted mono- and di-C 1 -C 6 alkylamino groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;

R 3 is halogen;

R 4 is selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 8 acyl, substituted or unsubstituted aryl acyl or substituted or unsubstituted heteroaryl acyl;

R 5 is selected from substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R 6 is selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 2 -C 6 alkynyl C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 acyl, substituted or unsubstituted arylacyl or substituted or unsubstituted heteroarylacyl;

The substitution means by OH; NH 2 ; C 1 -C 10 alkyl, alkenyl or alkynyl ; C 1 -C 10 alkylamino ; 20 alkoxy; C 1 -C 10 carbonyl; C 3 -C 10 cycloalkyl; 3-10-membered heterocyclic group with one or more heteroatoms selected from N, S, O, P; C 6 -C 20aryl ; C2 - C20heteroaryl ; nitrocyano, or halogen substituted.
A kind of application as claimed in claim 1, is characterized in that: described compound is the structure shown in formula II:
A kind of application as claimed in claim 1 is characterized in that: described compound is the structure shown in formula III:

where p is an integer from 0 to 3.
A kind of application as claimed in claim 1, is characterized in that: described compound is the structure shown in formula IV:

where p is an integer from 0 to 3.
A kind of application as claimed in claim 1 is characterized in that: described compound structure is:
A kind of application as claimed in claim 1 is characterized in that: described compound structure is:
A kind of application as claimed in claim 1 is characterized in that: described compound structure is:

wherein R 7 is H or a protecting group.
A kind of application as claimed in claim 1 is characterized in that: described compound structure is:
The application according to claim 6 or 7, wherein the compound structure is:

or
The use of any one of claims 1-7, wherein the medicament further comprises a pharmaceutically acceptable carrier.
The use of claim 8, wherein the medicament further comprises a pharmaceutically acceptable carrier.
The use of any one of claims 1-7, wherein the pain comprises: chronic pain or neuropathic pain; depression comprises: bipolar depression, major depressive disorder; improving anxiety and post-traumatic stress syndrome; improving cognitive Known functions include prevention or treatment of Alzheimer's dementia and Parkinson's.
The use of claim 8, wherein the pain comprises: chronic pain or neuropathic pain; depression comprises: bipolar depression, major depressive disorder; improving anxiety and post-traumatic stress syndrome; improving cognitive function including preventing Or treat Alzheimer's dementia, Parkinson's.