Long-acting, low-addictive compounds and methods for preparing same

Abstract

The present application relates to a compound having the effects of antidepressant, anesthetic, analgesic, cognitive function improvement, lung protection, prophylaxis or treatment of amyotrophic lateral sclerosis, or prophylaxis or treatment of complex regional pain syndrome. Compared with conventionally known HNK compounds, the compound of the present application has a longer duration of efficacy and is substantially non-addictive.

Description

[Technical Field]

[0001] The present application relates to the pharmaceutical field, specifically to long-acting, low-addictive compounds for treating depression, including complex regional pain syndrome (CRPS), and methods for preparing the same. [Background technology]

[0002] Ketamine is a representative intravenous anesthetic agent of the phencyclidine family commonly used clinically, and is one of the anesthetic agents for which clinical and basic research have developed relatively rapidly in recent years. In clinical practice, it is used to meet the anesthesia needs of pediatrics, obstetrics and gynecology, perioperative patients, and patients with special diseases due to its characteristics of rapid induction, short duration of action, fast resuscitation, and mild effects on the respiratory and circulatory systems.

[0003] Ketamine was first synthesized in 1962, used in humans in 1965, and officially approved for clinical use by the FDA in 1970. Its typical "dissociative anesthesia" and short-term, reliable pain relief made it temporarily popular, but its clinical use subsequently declined significantly due to the discovery of its psychological side effects and the rapid development of other intravenous anesthetics. Over the past decade, research into ketamine's dosage and the discovery of its anti-inflammatory, antidepressant, neuroprotective, and analgesic properties have led to a resurgence of interest in ketamine in the medical community.

[0004] Ketamine's effects on prehospital anesthesia and analgesia cannot be ignored due to its potent analgesia, amnesia, simultaneous maintenance of autonomic breathing and airway protective reflexes, and maintenance of hemodynamic stability. Ketamine has both neurotoxic and neuroprotective effects.

[0005] Ketamine affects postoperative cognitive function. One researcher conducted a test on 50 children who underwent ketamine anesthesia and found that ketamine general anesthesia reduced cognitive function 6 hours after surgery, but did not affect cognitive function 24 hours after surgery. Hudetz et al. found that administering 0.5 mg / kg of ketamine during general anesthesia induction reduced the incidence of postoperative cognitive dysfunction one week after cardiac surgery. In recent years, numerous clinical trials have demonstrated that a single, low-dose administration of ketamine during surgery reduces the incidence of postoperative cognitive dysfunction.

[0006] Ketamine has analgesic properties. Subanesthetic doses of ketamine are commonly used for antihyperalgesia and the treatment of acute and chronic pain. Studies have demonstrated that gargling with a ketamine-saline mixture before anesthesia induction significantly reduces the incidence and severity of postoperative sore throat caused by endotracheal intubation under general anesthesia. The use of opioids during surgery increases the postoperative dose of opioids for analgesia, an effect known as opioid tolerance. Clinical studies have shown that the use of ketamine not only prevents opioid tolerance but also reverses morphine tolerance and enhances the analgesic effects of morphine. Furthermore, some studies have demonstrated that the use of low-dose ketamine during surgery can prevent refentanil-induced postoperative hyperalgesia. Cagla et al. found that by administering 0.15 mg / kg of ketamine intravenously after surgery to patients undergoing knee arthroscopic surgery, ketamine significantly increased satisfaction with postoperative analgesia and had lower sedation scores than the ketamine-combined midazolam group.

[0007] Ketamine has a protective effect on the lungs. In recent years, ketamine has been found to have significant lung protective effects. Clinical trials have demonstrated that intravenous administration and nebulized inhalation before ventilation of one lung during thoracic surgery can reduce blood inflammatory factor levels, while nebulized inhalation has more benefits for the cardiovascular system and airway pressure, and the nebulized effect on the ventilation side of the lung is superior to that of nebulized in double-lung surgery. In clinical practice, ketamine is often used in emergency treatment of life-threatening asthma attacks that are ineffective against conventional treatment, and its use has also been recognized to improve prognosis.

[0008] Ketamine has antidepressant properties. In 2000, Berman et al. first reported that after a single intravenous injection of a subanesthetic dose of ketamine (0.5 mg / kg), more than 50% of patients experienced a 50% or greater reduction in their Hamilton Depression Rating Scale scores within 72 hours. In recent years, numerous animal and clinical studies have further demonstrated the antidepressant effects of ketamine. Ketamine is also used as an anesthesia for electroconvulsive shock therapy in depressed patients.

[0009] The patent application, bearing application number CN201280062294X and titled "Use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydrogenated and hydroxylated metabolites of (R,S)-ketamine 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 the NMDA receptor. The application reports that, based on ketamine, (2R,6R;2S,6S)-hydroxynorketamine (HNK) has been researched and synthesized. The compound is inactive at the NMDA receptor, thus avoiding these side effects. At the same time, the compound is reported to be effective in treating bipolar depression, severe depression, Alzheimer's disease, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, or neuropathic pain.

[0010] In this experimental study, we found that (2R,6R;2S,6S)-hydroxynorketamine (HNK) has a short duration of action after administration, essentially losing activity within one week, significantly limiting its long-term efficacy in the treatment of depression. At the same time, we found that the application of HNK can lead to a degree of addiction, adversely affecting the patient's physical and mental health. Therefore, modifying the structure of (2R,6R;2S,6S)-hydroxynorketamine (HNK) to obtain a drug with longer efficacy and less addiction potential holds great therapeutic potential. Summary of the Invention [Means for solving the problem]

[0011] The present application relates to compounds having the effects of antidepressant, ameliorating anxiety and post-traumatic stress syndrome, anesthetic, analgesic, improving cognitive function, protecting the lungs, preventing or treating amyotrophic lateral sclerosis, or preventing or treating complex regional pain syndrome.

[0012] Compared with known HNK compounds, the compounds of the present application have a longer duration of efficacy, specifically, HNK is metabolized and inactive within a week, whereas the duration of efficacy of the compounds of the present application can last for more than a week, specifically, for more than 7 days, more than 10 days, more than 14 days, etc. Furthermore, the compounds of the present application are substantially non-addictive, with their addictive potential being 2, 5, 10, or even 20 times lower than that of HNK compounds.

[0013] The present application provides a compound, a salt of a compound, a stereoisomer, or a tautomer, wherein the compound has the structure shown in Formula I. [ka] During the ceremony, m is an integer of 0 to 3, and n is an integer of 0 to 4; R1 and R2 each independently represent H, a halogen, a hydroxy group, an amino group, a cyano group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C2-C 10 one or more selected from a heterocyclic group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted mono- and di-C1-C6 alkylamino group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R3 is a halogen; R4 is selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C8 acyl group, a substituted or unsubstituted arylacyl group, or a substituted or unsubstituted heteroarylacyl group; R5 is a substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C2-C 10 selected from a heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R6 and R7 each independently represent H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C2-C 10 selected from a heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted C1-C8 acyl group, a substituted or unsubstituted arylacyl group, or a substituted or unsubstituted heteroarylacyl group; or R6 and R7 together with the N atom to which they are attached form a substituted or unsubstituted 3-10 membered monocyclic or bicyclic ring structure; The substitutions are OH; NH; C-C 10 Alkyl, alkenyl or alkynyl groups; C1-C 10 Alkylamine group;Mercapto group;C1-C 10 Alkylmercapto group; C1-C 20 Alkoxy group; C1-C 10 Carbonyl group; C3-C 10 Cycloalkyl groups; 3-10 membered heterocyclic groups containing one or more heteroatoms selected from N, S, O, and P; C6-C 20 Aryl group; C2-C 20 It refers to being substituted by a heteroaryl group; a nitrocyano group; or a halogen.

[0014] Preferably, the compound is characterized by the structure shown in formula II. [ka]

[0015] Preferably, the compound is characterized by the structure shown in formula III. [ka]

[0016] Preferably, the compound is characterized by the structure shown in formula IV. [ka]

[0017] Preferably, the compound is characterized in that it is the compound shown below. [ka]

[0018] Preferably, the compound is characterized in that it is the compound shown below. [ka]

[0019] The present application further provides a compound, a salt of the compound, a stereoisomer, or a tautomer, having the structural formula: [ka] where R8 is H or a protecting group.

[0020] Preferably, the compound, salt, stereoisomer, or tautomer of the compound is characterized by the structure shown below. [ka]

[0021] Preferably, the compound, salt, stereoisomer, or tautomer of the compound is characterized by the structure shown below. [ka] or [ka]

[0022] The present application further provides a pharmaceutical composition comprising the compound, salt, stereoisomer, or tautomer of the compound, optionally further comprising a pharmaceutically acceptable carrier.

[0023] The present application further provides a method for preparing a compound, characterized in that: [ka]

[0024] The use of any one of the above compounds in the preparation of a medicament for anesthesia, analgesia, improvement of cognitive function, lung protection, antidepressant, amelioration of anxiety and post-traumatic stress syndrome, amyotrophic lateral sclerosis, complex regional pain syndrome.

[0025] Here, the pain includes chronic pain or neuropathic pain, the depression includes bipolar depression and severe depression, the improvement of anxiety and post-traumatic stress syndrome, and the improvement of cognitive function include the prevention or treatment of Alzheimer's disease, Parkinson's disease, etc.

[0026] All of the above diseases also include preventive or therapeutic actions.

[0027] Stereoisomers of all the above compounds include enantiomers and diastereomers.

[0028] For all of the compounds described above, if the compounds exist in different tautomeric forms, the present application is not limited to any one specific tautomer, but includes all tautomeric forms.

[0029] All compounds described above include compounds with all possible isotopes of atoms present in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C. 13 C and 14 Contains C.

[0030] The present application further provides pharmaceutical compositions, wherein the compounds disclosed herein can be administered as pure chemicals, but are preferably administered as pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions comprising a compound or a pharmaceutical salt together with at least one pharmaceutical carrier. The pharmaceutical composition can comprise the compound or salt as the sole active agent, but preferably also comprises at least one other active agent. In some embodiments, the pharmaceutical composition is an oral dosage form comprising, in a unit dosage form, 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, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of another active agent.

[0031] The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, bucally, rectally, as an ophthalmic solution, or in other dosage unit formulations containing conventional pharmaceutical carriers. Pharmaceutical compositions can be prepared in any medicinal form, such as aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or eye drops. Some dosage forms, such as tablets and capsules, can be further subdivided into suitable dosage unit forms containing an appropriate amount of the active ingredient, such as an amount effective to achieve a desired purpose.

[0032] Carriers include excipients and diluents and should be of sufficiently high purity and very low toxicity to be compatible with administration to the patient being treated. Carriers may be inert or may have pharmaceutical benefits of their own.

[0033] Types of carriers include, but are not limited to, adhesives, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, flow aids, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in multiple categories, such as vegetable oils, which may be used as lubricants in some formulations and diluents in others. Exemplary pharmaceutical carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition without significantly affecting the activity of the compounds of the present application.

[0034] The compounds or salts of the present application may be the only active agent administered or may be administered together with other active agents. For example, the compounds of the present application may be administered together with another active agent selected from any one of the following:

[0035] antidepressants escitalopram oxalate, feroxitine, paroxetine, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, mirtazapine, venlafaxine, atomoxetine, bupropion, doxepin, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, donepezil, galantamine, memantine, rivastigmine, tramiprosate, or pharmaceutically active salts or prodrugs thereof, or combinations of the above; schizophrenia drugs : Aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine, olanzapine, loxapine, flupentioxol, perphenazine, haloperidol, chlorpromazine, fluphenazine, prolixin, paliperidone; Alzheimer's dementia medications: donepezil, rivastigmine, galantamine, memantine; ALS drugs : Riluzole; pain medication : Acetaminophen, aspirin, NSAIDs (including diclofenac, difluorobenzenesalicylic acid, etodolac, fenoprofen, flurbiprofen, biprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetinopioids, and Cox-2 inhibitors such as celecoxib), anesthetic pain medications (e.g., buprenorphine, butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, pethidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, and the central analgesic tramadol).

[0036] The above list of other active agents is illustrative, not comprehensive. Other active agents not included in the above list can be administered in combination with a compound of Formula I. In some embodiments, the other active agent is generally administered at less than the prescribed dose, and in some cases, less than the minimum approved dose, but can be administered in accordance with its approved regulatory information.

[0037] This application includes a method for treating depression, particularly bipolar depression and major depression, and especially treatment-resistant depression, wherein an effective amount of the compound is an amount effective to reduce depressive symptoms, where reduction in depressive symptoms is defined as a 50% or greater reduction in symptoms as determined by a depression symptom scale or HRSD. 17 7 or less, or QID-SR 16 The goal is to achieve a score of 5 or less on the ANOVA or a score of 10 or less on the MADRS.

[0038] The present application provides an amount effective to alleviate pain (or analgesic) symptoms, where alleviating pain symptoms means achieving a 50% or greater reduction in pain symptoms on a pain scale. Glossary:

[0039] "Stereoisomers" are compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0040] "Diastereomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures, such as electrophoresis, crystallization, or using chiral HPLC columns, if a resolving agent or chromatography is present.

[0041] "Enantiomers" refer to two stereoisomers of a compound that are not superimposable mirror images of one another. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when stereoselection or stereoorientation has been lost during a chemical reaction or process.

[0042] "Alkyl group" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, generally from 1 to about 12 carbon atoms. For example, as used herein, the term C1-C6 alkyl group refers to an alkyl group having from 1 to about 6 carbon atoms. As used herein, C0-C6 alkyl groups refer to alkyl groups having from 1 to about 6 carbon atoms. n When an alkyl group is used in conjunction with another group, such as a (phenyl)C0-C4 alkyl group, the specified group, in this case the phenyl group, is directly attached by a single covalent bond (C0) or by 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 groups.

[0043] "Alkenyl group" refers to straight and branched hydrocarbon chains containing 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. Preferably, alkenyl groups are lower alkenyl groups, such as C2-C8, C2-C6, and C2-C4 alkenyl groups, having from 2 to about 8 carbon atoms. Examples of alkenyl groups include vinyl, propenyl, and butenyl.

[0044] "Alkoxy" means an alkyl group as defined above with the specified 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.

[0045] Halogens are those known in the art, with F, Cl, Br, and I being preferred.

[0046] The term "heterocycle" refers to a 5- to 8-membered saturated, partially unsaturated, or 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 ring system and a 10- to 15-membered tricyclic ring system, wherein the system contains at least one heteroatom selected from N, O, and S in a polycyclic ring system, and each ring in the polycyclic ring system independently contains up to about 4 heteroatoms selected from N, O, and S. Unless otherwise specified, a heterocycle can be substituted at any heteroatom and carbon atom and attached to a group that provides a stable structure. When specified, heterocycles described herein may be substituted with carbon or nitrogen atoms as long as the resulting compound is stable. Optionally, the nitrogen atom in the heterocycle can be quaternized. Preferably, the total number of heteroatoms in the heterocyclic group is 4 or less, and preferably the total number of S and O atoms in the heterocyclic group is 2 or less, more preferably 1 or less. Examples of heterocyclic groups include pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolyl, pyrrolyl, pyrazolyl, benzo[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 groups.

[0047] The term "aryl or heteroaryl group" refers to 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, with the remaining ring atoms being carbon. If the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heteroaryl group is 2 or less. Particularly preferably, the total number of S and O atoms in the heteroaryl group is 1 or less. Optionally, the nitrogen atom in the heterocycle can be quaternized. Where specified, these heteroaryl groups can also be substituted with carbon or non-carbon atoms or groups. Such substitution can include fusion with a 5- to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O, and S, to form, for example, a [1,3]dioxazol[4,5-c]pyridyl group. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolyl, pyrrolyl, pyrazolyl, benzo[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline. Preferred aryl groups include phenyl and naphthyl.

[0048] "Depression" includes low mood, decreased interest in activities, sluggishness or irritability, changes in appetite, lack of concentration or indecisiveness, and excessive feelings of guilt or inferiority. Suicidal thoughts may occur in the presence of depression, bipolar depression, and other disease- or medical-related affective disorders, object-related affective disorders, and other unexplained affective disorders, and may coexist with various other mental disorders (including, but not limited to, psychotic disorders, cognitive disorders, eating disorders, anxiety disorders, and personality disorders). The longitudinal course, medical history, symptom types, and etiology of the illness help distinguish various forms of emotional illness from one another.

[0049] "Salts of compounds" refer to derivatives of the disclosed compounds in which the parent compound has been modified by the preparation of its non-toxic acid or base addition salts, and also to pharmaceutical solvates, including hydrates, of these compounds and their salts. Examples of pharmaceutical 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 combinations of one or more of the above salts. Pharmaceutical salts include non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids, and quaternary ammonium salts. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like. Other acceptable inorganic salts include metal salts such as sodium salts, potassium salts, and cesium salts, and alkaline earth metal salts such as calcium salts and magnesium salts, and combinations of one or more of the above salts.

[0050] Organic salts of compounds include 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, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n Salts prepared with organic acids such as —COOH (where n is 0-4); organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts; cyano acid salts such as arginine salts, aspartate salts, glutamate salts, and combinations of one or more of the above salts. [Brief explanation of the drawings]

[0051] [Figure 1] The antidepressant effects of different doses of the drug within 7 days. [Figure 2]The antidepressant effects of compounds C and D. [Figure 3] Compound I5 does not have sensitizing effects. [Figure 4] Compound C has behavioral sensitizing properties. [Figure 5] Compound D has behavioral sensitizing properties. [Figure 6] I5 does not have place preference effects in mice. [Figure 7] Compound C induces place preference. [Figure 8] Compound D induces place preference. DETAILED DESCRIPTION OF THE INVENTION

[0052] Example 1: Synthesis of (2R,6R)-6-hydroxynorketamine (HNK) [ka]

[0053] Step 1: Add 50 g of magnesium powder to a two-neck or three-neck flask. After the addition, slowly add a mixture of 119.2 g of bromocyclopentane and THF. After the addition is complete, reflux for 2-4 h to obtain 1.6 mol / L cyclopentyl Grignard reagent. To a mixture of THF and o-chlorobenzonitrile (50.0 g), add 840 mg of CuBr. Under ice bath conditions, add cyclopentyl Grignard reagent (1.6 mol / L, 280 ml). After the addition is complete, reflux for 1 h, cool to room temperature, add 100 ml of water, then add 200 ml of 15% dilute sulfuric acid solution. Stir overnight. The THF was spin-dried, extracted with EA, dried, and passed through a silica gel column to obtain 60 g of compound A, 2-chlorophenylcyclopentylmethanone, in 80% yield.

[0054] Step 2: Following a reported method (Bioorganic & Medicinal Chemistry 2013, 12, 5098), 20 g (96 mmol) of compound A was dissolved in 400 ml of EA. After dissolution, copper bromide (54 g, 242 mmol) was added. The mixture was heated under reflux for 3 hours and then cooled to room temperature. The solid insoluble matter was filtered through diatomaceous earth. Dichloromethane was added to wash the filter residue. The combined filtrate was concentrated to obtain compound B, 2-chlorophenyl(1-bromocyclopentyl)methanone, as a yellow oil. After passing through a silica gel column, 22 g of pure compound B was obtained in 80% yield.

[0055] Step 3: Ammonia gas was passed through 200 ml of aqueous ammonia until saturated, and compound B (10 g) was added. The mixture was stirred for 24 hours to precipitate compound C, which was filtered and dried to give brown solid compound C (7 g), which was directly used in the next step with a yield of 70%.

[0056] Step 4: Compound C (5 g) was dissolved in dry THF, and HCl gas was passed through until the solution reached a pH of 1. The solution was then spin-dried to obtain a solid hydrochloride salt. The solid hydrochloride salt was placed in a single-neck flask and placed in an oil bath at 190°C under nitrogen protection for approximately 20 minutes. The mixture was then cooled to room temperature and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with DCM, concentrated, and crystallized to obtain 2.9 g of compound D, racemic norketamine HNK, in a 75% yield. 1 H 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).

[0057] Step 5: Compound D (1.11 g, 5 mmol) was dissolved in 2 mL of methanol, L-tartaric acid (2.5 mmol) was added, and the mixture was stirred for 1 hour. The mixture was then added dropwise to 10 mL of acetone, allowed to stand, and filtered to obtain the L-tartrate salt. After recrystallization three times, the L-tartrate salt was neutralized with sodium bicarbonate solution and extracted with EA to obtain 165 mg of optically pure compound E, (R)-norketamine. The optical purity measured by chiral HPLC was 98.3% ee%, and the yield was 15%.

[0058] Chiral HPLC detection step: 1 mg of compound E and 1 mg of the control racemic compound D were dissolved in 1 mL of ethanol and subjected to normal-phase homogeneous analysis using an Agilent 1260-A high-performance liquid chromatography column. Chromatography column: Chiralcel-AD-H (4.6 mm x 250 mm), 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: The retention time of the R isomer was 6.8 min, and the retention time of the corresponding S isomer was 5.3 min.

[0059] Step 6: Compound E (2.23 g, 10 mmol) was added to 60 mL of THF, triethylamine (2.7 mL, 20 mmol) and BocO (3.3 g, 15 mmol) were added, and the mixture was refluxed for 6 h. The mixture was cooled, spun dry, and passed through a silica gel column to give 2.92 g of compound F in a 90% yield. 1 H 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 (100MHz, 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.

[0060] Step 7: Compound F (2.91 g, 9 mmol) was added to 60 ml of dry THF and cooled to -78 °C under argon protection. 5 ml of HMPA was added, followed by the slow dropwise addition of 2 M LDA in THF (12 ml, 24 mmol). The mixture was stirred for 30-40 min, then slowly warmed to -30 °C and stirred for 1 h. The mixture was then cooled again to -78 °C, trimethylchlorosilane TMSCl (2.6 g, 24 mmol) was added, the mixture was slowly warmed to -50 °C and stirred for 3 h, saturated ammonium chloride solution was added, the mixture was returned to room temperature, the THF solvent was concentrated, and EA was added for extraction. The organic phase was dried with anhydrous Na2SO4, the solvent was spin-dried, and the mixture was dried under vacuum. The resulting oil was then added to 100 ml of anhydrous DCM was added to dissolve the mixture, and the mixture was cooled to -15°C. Under argon protection, mCPBA (2.5 g, 11 mmol) was added and stirred for 1 h, then the mixture was warmed to room temperature. 50 ml of DCM was added and stirred for another 1 h. Saturated sodium thiosulfate and sodium bicarbonate solution (1:1) was then poured into the mixture, and the mixture was extracted with DCM. The solvent was spun dry and dried in vacuo. The resulting oil was dissolved in 100 ml of THF, and the mixture was cooled to -5°C. tetrabutylammonium fluoride (3 g, 11.4 mmol) was added and the mixture was stirred for 30 min. Saturated NaHCO3 solution was added and the mixture was extracted with EA. The solvent was spun dry and dried in vacuo. The mixture was passed through a silica gel column to obtain 1.92 g of compound G in a 65% yield. 1 H 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.

[0061] Step 8: Compound G (680 mg) was dissolved in 5 mL of dry THF, and the solution was stirred at room temperature for 4 h with HCl gas bubbled through until saturated. 20 mL of dry ether was added to precipitate crystals, which were then filtered to give 520 mg of compound H, the hydrochloride salt of (2R,6R)-6-hydroxynorketamine (HNK), in 95% yield. 1 H 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 I5

[0062] Compound G (170 mg, 0.5 mmol) was dissolved in 3 mL of dry THF, and dry triethylamine (0.28 mL, 2 mmol) was added. Then, triethylamine chloride (117 μL, 1 mmol) was added under ice bath conditions. The mixture was then slowly warmed to room temperature within 1 hour and stirred overnight. Sodium bicarbonate solution was then added, and the mixture was extracted with EA. The solvent was spin-dried, vacuum-dried, and passed through a silica gel column to obtain 184 mg of compound H4N-Boc-(2R,6R)-6-benzoyloxynorketamine, with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ8.22-8.19(m, 2H), 7.91(m, 1H), 7.69-7.64(m, 1H), 7.56-7.45(m, 4H), 6.75(br ,1H),5.54-5.50(m,1H),4.00(m,1H),2.54-2.52(m,1H),2.14-1.93(m,3H),1.86(m,1H),1.41(m,9H). 13C NMR(100MHz,CDCl3):δ202.2,164.9,153.3,133.2,131.4,131.1,129.9,12 9.7,129.5,128.3,128.0,126.1,79.2,73.8,67.2,36.6,34.8,28.2,19.0.

[0063] Compound H4 (180 mg) was dissolved in 3 mL of dry THF, and HCl gas was passed through the solution at room temperature until saturated. The solution was stirred for 4 h. 15–20 mL of dry ether was added to precipitate crystals, which were then vacuum filtered to give 128 mg of compound I4, (2R,6R)-6-benzoyloxynorketamine hydrochloride, in a yield of 83%. 1 H NMR(400MHz,CD3OD):δ9.25-9.20(brs,3H),8.21-8.19(m,2H),7.90(m,1H),7. 66-7.52(m,6H),5.57(m,1H),3.66(m,1H),2.58-2.43(m,2H),2.08-1.97(m,3H) 13 C NMR (100MHz, CD3OD): δ200.1,164.8,134.6,133.4,131.9,131.0,129.9,129.2,129.1,128.4,127.9,73.9,68.1,36.6,34.9,19.0.

[0064] [ka] Compound H (339 mg, 1 mmol) was dissolved in 8 mL of dry THF, and dry triethylamine (0.56 mL, 4 mmol) was added, followed by p-dimethylaminobenzoyl chloride (275 mg, 1.5 mmol). The mixture was refluxed overnight and the solvent was spin-dried. Sodium bicarbonate solution was then added, and the mixture was extracted with EA. The liquid was separated, the organic phase solvent was spin-dried, vacuum-dried, and passed through a silica gel column to obtain 292 mg of compound H5, N-Boc-(2R,6R)-6-p-dimethylaminobenzoyloxynorketamine. The yield was 60%. Compound H5 (292 mg) was dissolved in 6 mL of dry THF, and HCl gas was passed through at room temperature until saturated. The mixture was stirred for 4 h. 15–20 mL of dry ether was added to precipitate crystals, which were then vacuum-filtered to obtain 148 mg of compound I5, (2R,6R)-6-p-dimethylaminobenzoyloxynorketamine bishydrochloride. The yield was 54%. Compound I5 1 H NMR(400MHz,CD3OD):δ8.00(br,2H),7.79(m,1H),7.44-7.15(m,5H),5.45(m,1H),3.59- 3.56(m,6H),3.01-2.92(m,6H),2.38-2.35(m,1H),2.19-2.16(m,1H)1.96-1.93(m,3H). 13 C NMR (100MHz, CD3OD): δ200.8,164.5,150.6,134.4,132.4,132.1,131.0,129.4,128.5,115.8,74.1,67.8,43.7,37.0,35.3,19.2.

[0065] Example 3: Synthesis of Compounds C and D [ka] Compounds C and D can be prepared by the following preparation method. [ka]

[0066] Example 4: Activity Test 1. Forced Swim Experiment Mice were transferred to the experimental room 1 hour before the forced swim test (FST). The test was conducted under normal lighting conditions and monitored with a digital camera. During the test, each mouse was placed in a transparent glass cylinder (28.5 cm high, 14 cm diameter) filled with 20 cm of water (23 ± 1°C). On day 1, the mice were trained for 6 min and then removed from the cylinder. On day 2, the mice were administered saline, HNK, I5, C, or D, and the immobility time was tested after different time intervals. The immobility time was recorded using a Noldus system EthoVision XT (Noldus, The Netherlands) during the final 4 min of the entire 6-min swim test. This time was defined as passive floating, meaning there was no movement other than that required to keep the animal's head above the water surface. The water in the bottle was replaced every 2–3 trials. After the swim test, the mice were removed from the water and dried under an infrared lamp.

[0067] Mice were intragastrically administered 1 mg (A), 10 mg (B), and 30 mg (C) of HNK or I5, respectively, and the immobility time was measured 1 hour and 7 days later. The percentage of immobility time is expressed as mean ± SEM. *p<0.05, **p<0.01, compared with the baseline test. N=8 per group. Saline: saline group; I5: I5-treated group; HNK: 2R,6R-hydroxynorketonamine-treated group.

[0068] 2. Addictive research Materials and Methods Animals: 8-12 week-old C57BL / 6J male mice were randomly assigned to groups, with 10 mice weighing 18-22 g per group. They were housed at room temperature (22 ± 1°C), humidity (50 ± 10%), and lighting conditions (8:00 AM - 8:00 PM). The mice had free access to food and water and were allowed to acclimate to the experimental environment for at least 2-3 days before the experiment. All experiments were performed between 8:00 AM and 4:00 PM. Behavioral sensitization experiments:

[0069] 1.1 Measurement of spontaneous activity in small animals: The animal spontaneous activity infrared analysis system consists of a spontaneous activity box, an infrared probe device, and a data collection system. The size of the spontaneous activity box is 40 cm x 40 cm x 65 cm, light- and sound-proof, and equipped with a ventilation system. The animal's activity is recorded using an infrared probe, and the number of spontaneous activities is calculated. To measure the effects of drugs on spontaneous activity in mice, mice were randomly divided into four groups of 10 mice each. Groups: vehicle, I5, C, D (5.0, 10.0, 30.0 mg / kg), and mor (10 mg / kg). Each group was intragastrically administered once daily in the morning for 7 consecutive days, followed by a 7-day drug-free period. On the 15th day, mice in each group were stimulated by intragastrically administering Veh and drugs (5.0, 10.0, 30.0 mg / kg). On days 1, 7, and 15, spontaneous activity of the mice was measured within 1 hour immediately after administration.

[0070] 1.2 CPP Experiment: The three-chamber CPP system consisted of two black and white boxes (25cm x 25cm x 30cm) separated by a central box (10cm x 25cm x 30cm). During the experiment, mice were placed in the central box and could freely shuttle between the two boxes. A shuttle door, measuring 5cm x 5cm, was provided between each of the two boxes and the central box. The experiment employed a bias program, divided into three stages: pre-test, training, and test. Environmental conditions within the boxes, such as light, color, and odor, were matched throughout the entire experimental process.

[0071] Pre-test: On days 1-3, the partitions in the boxes were opened, and all mice were given a subcutaneous injection of saline. They were then placed in the center box and allowed to move freely within the box for 15 minutes, once a day for three consecutive days. The time spent in the black and white boxes was recorded to determine the mice's natural preference. The mice were then trained using the non-natural preference box as the drug-contingent box.

[0072] Training period: On days 4-9, the shuttle door was closed and the mice were randomly divided into groups of 10 each, containing Veh, mor, I5, C, D (5.0, 10.0, 30.0 mg / kg), and mor (10 mg / kg). In the morning on odd-numbered days, all mice were intragastrically administered saline, followed by 45 minutes in the non-concomitant drug chamber (black box). In the afternoon on odd-numbered days, Veh, mor, I5, C, and D (5.0, 10.0, 30.0 mg / kg) were intragastrically administered, followed by 45 minutes in the concomitant drug chamber (white box). The training order was reversed on even-numbered days. The interval between morning and afternoon training was at least 6 hours, and the training time was fixed each day. Each group of 10 mice was trained for 6 consecutive days.

[0073] Test period: On the 10th day, the partition was removed, and the mice were placed in the central box and allowed to move freely. Meanwhile, the time spent by the mice in the white box was recorded within 15 minutes.

[0074] Statistical analysis: Experimental data are expressed as x ± SEM. Statistical analysis was performed using GraphPad software. Comparisons between two groups were performed using the t-test, and comparisons between multiple groups were performed using one-way ANOVA analysis, followed by pairwise comparisons using the LSD method.

[0075] 3. Place preference experiment Place preference was tested using a three-chamber system. Mice were trained in a non-natural preference box as the contingent drug box. During the training period, mice were administered saline (Veh), morphine (morphine, 10 mg / kg), I5, C, and D (5.0, 10.0, 30.0 mg / kg), respectively. After six consecutive days of training, mice were tested and their time spent in the white box was recorded for 15 min.

[0076] *P<0.05 (n=10) compared with the Veh group.

[0077] Example 5: Experimental Results 1. Test results of depression-like behavior in mice: Neither 1 mg HNK nor I5 had any antidepressant effect, while 10 mg HNK and I5 both had antidepressant effect, with I5 having a long-lasting effect and the efficacy not substantially diminishing within 7 days, whereas HNK's efficacy rapidly diminished within 7 days and essentially no effect by day 7. 30 mg HNK and I5 both had antidepressant effect, with I5 having a long-lasting effect and the efficacy not substantially diminishing within 7 days, whereas HNK's efficacy rapidly diminished within 7 days and essentially no effect by day 7.

[0078] Compounds C and D have no antidepressant effect at 30 mg.

[0079] Compared with the HNK-treated group, the I5-treated group still had a significant antidepressant effect 7 days after administration, as evidenced by a reduction in the immobility time of the animals during forced swimming. The immobility time of the I5 group was shorter. There was no significant difference between the 10 mg and 30 mg treatment groups, with the 30 mg group showing a stronger tendency for reduction. Neither Compound C nor D had any antidepressant effect.

[0080] 2. Addiction Experiments Different doses of I5 (5 mg, 10 mg, 30 mg) did not induce behavioral sensitization in mice.

[0081] Different doses (5 mg, 10 mg, 30 mg) of C and D induce behavioral sensitization in mice.

[0082] 3. Place preference experiment Different doses of I5 (5 mg, 10 mg, 30 mg) had no place preference effect on mice.

[0083] Different doses (5 mg, 10 mg, 30 mg) of C and D induce place preference in mice.

[0084] The various technical features in the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of each technical feature in the above embodiments are described. However, as long as there is no contradiction in the combinations between the technical features, they should all be considered within the scope described in this specification.

[0085] The above examples only represent some embodiments of the present application, and the description is specific and detailed, but should not be understood as a limitation on the patent scope of the present application. It should be noted that those skilled in the art can make some modifications and improvements without departing from the gist of the present application, and all of these should be considered to be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the scope of the attached claims. The present invention provides, for example, the following items. (Item 1) A compound, a salt of the compound, a stereoisomer, or a tautomer having the structure of Formula I. [ka] (In the formula, m is an integer of 0 to 3, and n is an integer of 0 to 4; R 1 and R 2 are each independently H, a halogen, a hydroxy group, an amino group, a cyano group, a substituted or unsubstituted C 1 -C 6 Alkyl group, substituted or unsubstituted C 2 -C 6 Alkenyl group, substituted or unsubstituted C 2 -C 6 Alkynyl group, substituted or unsubstituted C 3 -C 10 Cycloalkyl groups, substituted or unsubstituted C 2 -C 10 Heterocyclic groups, substituted or unsubstituted C 1 -C 6 Alkoxy groups, substituted or unsubstituted mono- and di-C 1 -C 6 one or more selected from an alkylamino group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R 3 is a halogen; R 4 is H, substituted or unsubstituted C 1 -C 6 Alkyl group, substituted or unsubstituted C 1 -C 8 acyl group, substituted or unsubstituted aryl acyl group, or substituted or unsubstituted heteroaryl acyl group; R 5 is a substituted or unsubstituted C 3 -C 10 Cycloalkyl groups, substituted or unsubstituted C 2 -C 10 selected from a heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R 6 and R 7 are each independently H, substituted or unsubstituted C 1-C 6 Alkyl group, substituted or unsubstituted C 2 -C 6 Alkenyl group, substituted or unsubstituted C 2 -C 6 Alkynyl group, substituted or unsubstituted C 3 -C 10 Cycloalkyl groups, substituted or unsubstituted C 2 -C 10 Heterocyclic groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted C 1 -C 8 acyl group, substituted or unsubstituted aryl acyl group, or substituted or unsubstituted heteroaryl acyl group; or R 6 and R 7 together with the N atom to which they are attached form a substituted or unsubstituted 3-10 membered monocyclic or bicyclic ring structure; The substitutions are OH;NH 2 ;C 1 -C 10 an alkyl group, an alkenyl group, or an alkynyl group; C 1 -C 10 Alkylamine group; Mercapto group; C 1 -C 10 Alkylmercapto group; C 1 -C 20 Alkoxy group; C 1 -C 10 Carbonyl group; C 3 -C 10 Cycloalkyl groups; 3-10 membered heterocyclic groups having one or more heteroatoms selected from N, S, O, and P; C 6 -C 20 Aryl group; C 2 -C 20 It refers to being substituted by a heteroaryl group; a nitrocyano group; or a halogen. (Item 2) A compound, a salt of the compound, a stereoisomer, or a tautomer according to item 1, characterized in that it has the structure shown in formula II.

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Claims

1. A compound, a salt of the compound, a stereoisomer, or a tautomer having the structure shown in Formula IV. 【Chemistry 19】 IV (In the formula, R ６ and R ７ are each independently C １ -C ６ alkyl group)

2. A compound characterized by being a compound represented by the following formula: 【Chemistry 20】

3. The compound according to claim 1, characterized in that it is a compound represented by the following formula: 【Chemical 21】

4. A pharmaceutical composition comprising a compound, a salt of the compound, a stereoisomer, or a tautomer of the compound according to any one of claims 1 to 3, optionally further comprising a pharmaceutically acceptable carrier.

5. As shown in the formula below, Compound G was reacted with p-dimethylaminobenzoyl chloride in THF solvent to give Compound H. ５ Obtain; Compound H ５ and HCl gas in THF solvent to give Compound I ５ Compound I is obtained by ５ Method for preparation of 【Chemical 26】

6. The compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 for the prevention or treatment of anesthesia, analgesia, improvement of cognitive function, lung protection, antidepressant, improvement of anxiety and post-traumatic stress syndrome, amyotrophic lateral sclerosis, and complex regional pain syndrome.

7. The compound or pharmaceutical composition according to claim 6, wherein the complex regional pain includes chronic pain or neuropathic pain, the depression in the antidepressant treatment includes bipolar depression and severe depression, and the improvement of cognitive function includes the prevention or treatment of Alzheimer's disease and Parkinson's disease.

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