WO2022041172A1 - Utilisation d'un composé à action prolongée et à faible dépendance dans la préparation d'un médicament - Google Patents

Utilisation d'un composé à action prolongée et à faible dépendance dans la préparation d'un médicament Download PDF

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WO2022041172A1
WO2022041172A1 PCT/CN2020/112363 CN2020112363W WO2022041172A1 WO 2022041172 A1 WO2022041172 A1 WO 2022041172A1 CN 2020112363 W CN2020112363 W CN 2020112363W WO 2022041172 A1 WO2022041172 A1 WO 2022041172A1
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substituted
unsubstituted
compound
application
pain
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PCT/CN2020/112363
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Chinese (zh)
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李书鹏
周强
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深圳瑞健生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present application relates to the field of medicine, in particular to the application of a long-acting and low-addiction compound in the treatment or prevention of depression, including complex regional pain syndrome (CRPS) and other diseases.
  • CRPS complex regional pain syndrome
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • CNS central nervous system
  • This application relates to an antidepressant, improving anxiety and post-traumatic stress syndrome, anesthesia, analgesia, improving cognitive function, lung protection, preventing or treating amyotrophic lateral sclerosis or preventing or treating complex regional pain Syndromic 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.
  • 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.
  • 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 and R 7 are each independently 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 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 aryl acyl or substituted or unsubstituted heteroaryl acyl;
  • 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 structure
  • the above-mentioned compound is characterized in that it is the structure shown in formula II:
  • the above-mentioned compound is characterized in that it is the structure shown in formula III:
  • the above-mentioned compound is characterized in that it is the structure shown in formula IV:
  • the above-mentioned compound is characterized in that it is the following compound:
  • 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:
  • R8 is H or a protecting group.
  • the above-mentioned compound, compound salt, stereoisomer or tautomer is characterized by the following structure:
  • the above-mentioned compound, compound salt, stereoisomer or tautomer is characterized by the following structure:
  • the present application also provides a pharmaceutical composition, which is characterized by comprising the above-mentioned compound, compound salt, stereoisomer, or tautomer, optionally further comprising a pharmaceutically 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 .
  • 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.
  • Stereoisomers of all the above compounds include enantiomers and diastereomers.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • 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.
  • 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.
  • 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.
  • 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 Phenylpine, 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.
  • active agents are exemplary and not comprehensive.
  • Other active agents not included in the above list can be administered in combination with compounds of formula I.
  • 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.
  • Steps 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a heterocycle can be attached to a group where it is substituted at any heteroatom and carbon atom and results in a stable structure.
  • 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.
  • 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.
  • 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.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heteroaryl group is not 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.
  • substitution may include fusing 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, [1,3]dioxin Azolo[4,5-c]pyridyl.
  • heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , and 5,6,7,8-tetrahydroisoquinoline.
  • 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 .
  • 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.
  • non-toxic acid salts include those derived from inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; other acceptable inorganic salts include metal salts such as: sodium salts, potassium salts, Cesium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc., and combinations comprising one or more of the foregoing salts.
  • inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.
  • other acceptable inorganic salts include metal salts such as: sodium salts, potassium salts, 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 salt
  • 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.
  • 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 for 3 hours. , then cooled to room temperature, the solid insolubles were filtered with celite, the filter residue was washed with dichloromethane and then combined with the filtrate and concentrated to obtain a yellow oily compound B 2-chlorophenyl(1-bromocyclopentyl)methanone. 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.
  • 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.
  • 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.
  • 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.
  • 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: ⁇ 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).
  • 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, I5, C, D.
  • FST forced swim test
  • Immobility time defined as passive floatation
  • mice 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°C), 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.
  • 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 40cmX 40cm X 65cm, with sound insulation and light insulation, and ventilation.
  • the activity status of the animals was recorded by the infrared probe, and the number of spontaneous activities of the animals was calculated.
  • the mice were randomly divided into 4 groups with 10 mice in each group. Grouping: vehicle, I5, C, D (5.0, 10.0, 30.0 mg/kg), mor (10 mg/kg).
  • 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.
  • 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.
  • mice 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, I5, C, D (5.0, 10.0, 30.0 mg/kg), mor (10 mg/kg), 10 mice in each group.
  • All mice were given normal saline by intragastric administration, and immediately placed in the non-accompanied medicine box (black box) for 45 minutes; in the afternoon of odd-numbered days, they were administered with Veh, mor, I5, C, D (5.0, 10.0, 30.0 mg/ 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.
  • 1mgHNK and I5 have no antidepressant effect; 10mgHNK and I5 have antidepressant effect, I5 has a long-acting effect, the efficacy basically does not decay within 7 days, while the efficacy of HKN decays rapidly within 7 days, and basically has no effect on the 7th day. 30mg HNK and I5 have antidepressant effects, I5 has a long-term effect, and the effect is basically not attenuated within 7 days, while the effect of HKN decays rapidly within 7 days, and there is basically no effect on the 7th day.
  • the I5-treated group Compared with the HNK-treated group, the I5-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 I5 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.

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Abstract

La présente invention concerne l'utilisation d'un composé dans un médicament anti-dépresseur, d'anesthésie, d'analgésie, d'amélioration de la fonction cognitive, de protection des poumons, et de traitement ou de prévention de la sclérose latérale amyotrophique ou du syndrome de douleur régionale complexe. Le composé selon la présente invention présente un temps d'efficacité plus Long que les composés HNK existants, et le composé selon la présente invention ne produit pratiquement pas de dépendance.
PCT/CN2020/112363 2020-08-31 2020-08-31 Utilisation d'un composé à action prolongée et à faible dépendance dans la préparation d'un médicament WO2022041172A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104395283A (zh) * 2011-10-14 2015-03-04 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮、(s)-脱氢去甲氯胺酮以及(r,s)-氯胺酮的其他立体异构脱氢和羟基化代谢物在治疗忧郁症和神经性疼痛中的应用
CN109311801A (zh) * 2016-03-25 2019-02-05 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮和(2s,6s)-羟基去甲氯胺酮的晶型和合成方法
CN110167541A (zh) * 2016-10-27 2019-08-23 国立大学法人千叶大学 (s)-去甲氯胺酮及其盐作为药物的应用
CN110218157A (zh) * 2018-03-01 2019-09-10 江苏恒瑞医药股份有限公司 一种r-氯胺酮及其可药用盐的制备方法
CN110559282A (zh) * 2019-08-02 2019-12-13 华中科技大学同济医学院附属同济医院 去甲氯胺酮在制备抗抑郁的药物中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104395283A (zh) * 2011-10-14 2015-03-04 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮、(s)-脱氢去甲氯胺酮以及(r,s)-氯胺酮的其他立体异构脱氢和羟基化代谢物在治疗忧郁症和神经性疼痛中的应用
CN109311801A (zh) * 2016-03-25 2019-02-05 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮和(2s,6s)-羟基去甲氯胺酮的晶型和合成方法
CN110167541A (zh) * 2016-10-27 2019-08-23 国立大学法人千叶大学 (s)-去甲氯胺酮及其盐作为药物的应用
CN110218157A (zh) * 2018-03-01 2019-09-10 江苏恒瑞医药股份有限公司 一种r-氯胺酮及其可药用盐的制备方法
CN110559282A (zh) * 2019-08-02 2019-12-13 华中科技大学同济医学院附属同济医院 去甲氯胺酮在制备抗抑郁的药物中的应用

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