WO2022041172A1 - Use of long-acting and low-addiction compound in preparation of medicament - Google Patents
Use of long-acting and low-addiction compound in preparation of medicament Download PDFInfo
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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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- pain
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- 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.
Abstract
The present application relates to use of a compound in a medicament for anti-depression, anesthesia, analgesia, improvement of cognitive function, lung protection, and treatment or prevention of amyotrophic lateral sclerosis or complex regional pain syndrome. The compound of the present application has a longer efficacy time than the existing HNK compounds, and the compound of the present application substantially does not produce addiction.
Description
本申请涉及药物领域,具体涉及一种长效低成瘾性化合物在治疗或预防抑郁症,包括复杂性区域疼痛综合症(CRPS)等疾病中的应用。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.
氯胺酮(ketamine)是临床常用的苯环己哌啶类静脉麻醉药物的代表,是近年来临床与基础研究发展较快的麻醉剂之一。在临床实践中,因为其具有诱导迅速、作用时间较短、苏醒较快、对呼吸和循环系统影响较轻等特点,常用于满足儿科、产科、围手术期及特殊疾病患者的麻醉需求。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.
氯胺酮最早于1962年合成,1965年用于人体,1970年被FDA正式批准用于临床。其典型的“分离麻醉”及短效确切的镇痛使得它曾红极一时,但是随后被发现精神方面的副作用及其他静脉麻醉药物的迅速发展使得氯胺酮的临床使用大大减少。近10年来,随着对氯胺酮用法用量的研究,及其抗炎,抗抑郁,神经保护、镇痛等的作用被发现,医学界对氯胺酮的兴趣重新高涨。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.
一直以来,氯胺酮具有的强力镇痛,遗忘,同时能保留自主呼吸和气道保护性反射,保持血流动力学稳定等作用使得氯胺酮在院前麻醉镇痛中的作用不容忽视。氯胺酮同时具有神经毒性和神经保护作用。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.
氯胺酮对术后认知功能具有影响。有研究者对50例接受氯胺酮麻醉的患儿进行测试后发现,氯胺酮全麻可以降低患儿术后6h的认知功能,但对术后24h的认知功能无影响。Hudetz等发现在全麻诱导时给予0.5mg/kg氯胺酮,能够降低心脏手术术后1周的术后认知功能障碍发生率。近年来,众多的临床实验都证实,术中单次小剂量的应用氯胺酮能够降低术后手术后认知功能障碍发生率。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.
氯胺酮具有镇痛作用。亚麻醉剂量的氯胺酮常被用于抗痛觉过敏,及急慢性疼痛的治疗。研究证实麻醉诱导前氯胺酮盐水混合液漱口,能明显降低全麻气管插管引起的术后咽痛发生率及严重程度。术中阿片类药物使用使得术后阿片类药物镇痛用量增加,这种效应叫做阿片类药物耐受。而临床发现氯胺酮的使用能 够防止阿片类药物耐受,还能够逆转吗啡耐受,增强吗啡的镇痛效果。亦有研究证实小剂量氯胺酮术中应用能够防止瑞芬太尼诱导的术后痛觉过敏。Cagla等对膝关节镜手术的病人术后静注氯胺酮0.15mg/kg发现,氯胺酮能显著提高术后镇痛满意度,且较氯胺酮复合咪达唑仑组镇静评分更低。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.
氯胺酮具有肺保护作用。近年来,氯胺酮被发现具有显著地肺保护作用。有临床实验证实,胸科手术中单肺通气前经静脉和雾化都能够降低血中炎症因子的水平,而雾化吸入对心血管系统和气道压更有好处,而肺通气侧雾化效果优于双肺雾化。氯胺酮在临床中也常用于当常规治疗无效的致死性的哮喘发作的抢救,公认的其使用能够改善预后。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.
氯胺酮具有抗抑郁的作用。2000年Berman等首次报道单次静脉注射亚麻醉剂量的氯胺酮(0.5mg/kg)后72h内超过50%的患者汉密顿抑郁量表评分减低50%以上。近几年,较多的动物和临床研究进一步证实氯胺酮的抗抑郁效应。氯胺酮也被用于抑郁病人电休克治疗的麻醉。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.
申请号为CN 201280062294X,发明名称为(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的专利申请,公开了CNS(中枢神经系统)副作用与(R,S)-氯胺酮对于NMDA受体的活性有关,在该申请中以氯胺酮为基础,研究和合成了(2R,6R;2S,6S)-羟基去甲氯胺酮(HNK),该化合物对于NMDA受体没有活性,从而避免了可能的副作用,同时该化合物据称具有治疗两极忧郁症、重度抑郁症、阿尔茨海默尔痴呆、肌萎缩侧索硬化症、复杂性区域疼痛综合症(CRPS)、慢性疼痛、或神经性疼痛的作用。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.
我们在实验研究中发现,(2R,6R;2S,6S)-羟基去甲氯胺酮(HNK)在给药后,药效持续时间并不长,1周内就基本没有活性,这严重限制了治疗抑郁症时所希望的长效效果。同时我们的研究还发现在应用HNK时会产生一定的成瘾性,对患者身心造成不良影响。因此如何对(2R,6R;2S,6S)-羟基去甲氯胺酮(HNK)进行结构修饰,以获得更长药效和更低成瘾性的药物,将具有巨大的治疗潜力。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.
发明内容SUMMARY OF THE INVENTION
本申请涉及一种具有抗抑郁、改善焦虑和创伤后应激综合症、麻醉、镇痛、改善认知功能、肺保护、、预防或治疗肌萎缩侧索硬化症或预防或治疗复杂性区域疼痛综合症的化合物。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.
本申请的化合物与现有已知的HNK类化合物相比具有更长的药效时间,具体表现在HNK在一周内即代谢,没有活性,而本申请的化合物药效时间可以持续1周以上,具体的为7天以上、10天以上、14天以上等。而且,本申请的化合物基本不会产生成瘾性,其成瘾性比HNK类化合物低2倍、5倍、10倍、或20倍。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.
本申请提供了一种化合物、化合物的盐、立体异构体、或互变异构体,所述化合物具有式I所示结构: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:
其中:in:
其中m为0-3的整数,n为0-4的整数;Where m is an integer from 0 to 3, and n is an integer from 0 to 4;
R
1和R
2各自独立地选自H、卤素、羟基、氨基、氰基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
10杂环基、取代或未取代的C
1-C
6烷氧基、取代或未取代的单-和二-C
1-C
6烷基氨基、取代或未取代的芳基、取代或未取代的杂芳基中的1种或多种;
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为卤素;
R 3 is halogen;
R
4选自H、取代或未取代的C
1-C
6烷基、取代或未取代的C
1-C
8酰基、取代或未取代的芳基酰基或取代或未取代的杂芳基酰基;
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选自取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
10杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
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和R
7各自独立地选自H、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
10环烷基、取代或未取代的C
2-C
10杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的C
1-C
8酰基、取代或未取代的芳基酰基或取代或未取代的杂芳基酰基;
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;
或者R
6和R
7与其所连的N原子一起形成取代或未取代的3-10元单环或双环结构;
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 structure;
所述取代是指被OH;NH
2;C
1-C
10烷基、烯基或炔基;C
1-C
10烷基胺基;巯基;C
1-C
10烷基巯基;C
1-C
20烷氧基;C
1-C
10羰基;C
3-C
10环烷基;具有选自N、S、O、P中一个多个杂原子的3-10元杂环基;C
6-C
20芳基;C
2-C
20杂芳基;硝基氰基、或卤素取代。
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.
优选的,如上所述的化合物,其特征在于其为式II所示结构:Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula II:
优选的,如上所述的化合物,其特征在于其为式III所示结构:Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula III:
优选的,如上所述的化合物,其特征在于其为式IV所示结构:Preferably, the above-mentioned compound is characterized in that it is the structure shown in formula IV:
优选的,如上所述的化合物,其特征在于为如下所示化合物:Preferably, the above-mentioned compound is characterized in that it is the following compound:
优选的,如上所述的化合物,其特征在于为如下所示化合物:Preferably, the above-mentioned compound is characterized in that it is the following compound:
本申请还提供了一种化合物、化合物的盐、立体异构体、或互变异构体,其结构式如下:The application also provides a compound, a salt of the compound, a stereoisomer, or a tautomer, and its structural formula is as follows:
其中R
8为H或保护基团。
wherein R8 is H or a protecting group.
优选的,如上所述的化合物、化合物的盐、立体异构体、或互变异构体,其特征在于为如下结构:Preferably, the above-mentioned compound, compound salt, stereoisomer or tautomer is characterized by the following structure:
优选的,如上所述的化合物、化合物的盐、立体异构体、或互变异构体,其特征在于为如下结构:Preferably, the above-mentioned compound, compound salt, stereoisomer or tautomer is characterized by the following structure:
或者or
本申请还提供了一种药物组合物,其特征在于包括上述所述的化合物、化合物的盐、立体异构体、或互变异构体,任选的还包含药学上可接受的载体。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.
本申请还提供了一种化合物的制备方法,其特征在于:The application also provides a preparation method of a compound, characterized in that:
如前所述的任一化合物在制备麻醉、镇痛、改善认知功能、肺保护、抗抑郁、改善焦虑和创伤后应激综合症、肌萎缩侧索硬化症、复杂性区域疼痛综合症药物中的应用。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 .
其中所述疼痛包括:慢性疼痛或神经性疼痛;抑郁症包括:两极忧郁症、重度抑郁症;改善焦虑和创伤后应激综合症;改善认知功能包括预防或治疗阿尔茨海默尔痴呆、帕金森等。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.
上述所有疾病,也涵盖了预防或治疗作用。All of the above diseases also cover preventive or therapeutic effects.
上述所有化合物的立体异构体包括对映异构体、非对映异构体。Stereoisomers of all the above compounds include enantiomers and diastereomers.
上述所有化合物在化合物以不同互变异构形式存在的情况下,本申请不限于任一种具体互变异构体,而是包括所有的互变异构体形式。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.
上述所有化合物包括具有在化合物中出现的原子的所有可能的同位素的化合物。同位素包括具有相同原子序数但是不同质量数的那些原子。通过一般实例, 在没有限制的情况下,氢的同位素包括氚和氘,并且碳的同位素包括
11C、
13C和
14C。
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 .
本申请还提供了一种药物组合物,本文中公开的化合物可以以纯化学品给予,但优选作为药物组合物给予。因此,本公开提供了包括化合物或药用盐连同至少一种药用载体的药物组合物。药物组合物可以包含化合物或盐作为唯一的活性剂,但是优选包含至少一种其他活性剂。在某些实施方式中,药物组合物是在单位剂型中包含约0.1mg至约1000mg、约1mg至约500mg、或约10mg至约200mg的式I的化合物以及可选的约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg、或约200mg至约600mg的其他活性剂的口服剂型。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.
本文中公开的化合物可以以包含常规药用载体的剂量单位制剂口服、局部、非肠道、通过吸入或喷雾、舌下、透皮、通过口腔给予、直肠、作为眼用溶液、或通过其它方式来给予。可以将药物组合物配制成任何药用形式,如:气雾剂、乳膏剂、凝胶剂、丸剂、胶囊剂、片剂、糖浆剂、透皮贴剂、或眼用溶液。诸如片剂和胶囊剂的一些剂型可以再分成包含诸如达到期望目的的有效量的适当量活性组分的适当剂量单位剂型。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.
载体包括赋形剂和稀释剂,并且必须具有足够高的纯度和十分低的毒性以使它们适于被给予待治疗的患者。载体可以是惰性的或其可以本身具有药用益处。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.
载体的种类包括但不限于:粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、滑润剂、防腐剂、稳定剂、表面活性剂、制片剂、以及润湿剂。一些载体可以列在多于一种的类别中,如:植物油可以在一些制剂中用作滑润剂并在其他制剂中用作稀释剂。示例性药用载体包括糖、淀粉、纤维素、西黄蓍胶粉(powdered tragacanth)、麦芽、明胶、滑石和植物油。可选的活性剂可以包括在药物组合物中,其基本上不影响本申请的化合物的活性。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.
本申请的化合物或盐可以是被给予的唯一活性剂或可以连同其他活性剂被给予。例如,本申请的化合物可以连同另一选自以下中的任一种的活性剂被给予: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:
抗抑郁剂:草酸依地普仑、费洛克汀、帕罗西汀、度洛西汀、舍曲林、西酞普兰、丁氨苯丙酮、文拉法辛、度洛西汀、纳屈酮、米氮平、文拉法辛、阿托莫西汀、丁氨苯丙酮、多虑平、阿米替林、氯米帕明、去甲替林、丁螺环酮、阿立哌唑、氯氮平、克塞平、奥氮平、喹硫平、利培酮、齐拉西酮、酰胺咪嗪、 加巴喷丁、拉莫三嗪、苯妥英、普瑞巴林、多奈哌齐、加兰他敏、美金刚、卡巴拉汀、高牛磺酸(tramiprosate)、或它们的药物活性盐或前药、或上述的组合;
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;
精神分裂症药物:阿立哌唑、鲁拉西酮、阿塞那平、氯氮平、齐拉西酮、利培酮、喹硫平、三氟啦嗪、奥氮平、克塞平、氟哌噻吨(flupentioxol)、佩吩嗪、氟哌丁苯、氯丙嗪、氟非那嗪、氟奋乃静、帕潘立酮;
Schizophrenia drugs : aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine, olanzapine, clozapine, Flupentioxol, Perphenazine, Haloperidol, Chlorpromazine, Fluphenazine, Fluphenazine, Paliperidone;
阿尔茨海默尔痴呆药物:多奈哌齐、卡巴拉汀、加兰他敏、美金刚;Alzheimer's dementia drugs: donepezil, rivastigmine, galantamine, memantine;
ALS药物:利鲁唑;
ALS drugs : riluzole;
疼痛药物:醋氨酚、阿斯匹林、NSAIDS,包括:双氯芬酸、二氟苯水杨酸、依托度酸、非诺洛芬、氟比洛芬、布洛芬、茚甲新、酮洛芬、酮咯酸、甲氯芬那酸、甲灭酸、美洛昔康、萘丁美酮、萘普生、奥沙普秦、苯基丁氮酮、吡罗昔康、舒林酸、Tolmetinopiods、Cox-2抑制剂如塞来昔布,以及麻醉疼痛药物如:丁丙诺啡、布托啡诺、可待因、二氢可待因酮、氢化吗啡酮、羟甲左吗喃、哌替啶、美沙酮、吗啡、纳布啡、氧可酮、氧吗啡酮、镇痛新、丙氧芬、中枢性镇痛反胺苯环醇。
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.
其他活性剂的前述列表是示例性的而不是全面地包括。以上列表中未包含的其他的活性剂可以结合式I的化合物被给予。尽管在一些实施方式中,其他活性剂将以小于一般规定的剂量并且在一些情况下小于批准剂量的最小值给予,但是可以根据它的批准规定信息来给予其他活性剂。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.
本申请包括治疗抑郁症,尤其是治疗两极忧郁症和重度抑郁症的方法,特别是治疗难治性抑郁症(treatment-resistant depression)的方法,其中,化合物的有效量是有效减少抑郁症状的剂量,其中,抑郁症状的减少是达到在忧郁症状等级量表上所确定的症状的50%或更高的减少,或在HRSD
17上小于或等于7的分数,或在QID-SR
16上小于或等于5、或在MADRS上小于或等于10。
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.
本申请提供了有效减少疼痛(或镇痛)症状的量;其中,疼痛症状的减少是达到在疼痛等级量表上疼痛症状减少50%或更高。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.
术语约定:Terminology convention:
“立体异构体”是具有相同化学组成但原子或基团在空间中的排布不同的化合物。"Stereoisomers" are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.
“非对映异构体”是具有两个或更多手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体具有不同物理性能,例如:熔点、沸点、谱特性和反应活性。在拆分剂或色谱存在的情况下,使用诸如手性HPLC柱,可以在诸如电泳、结晶的高分辨分析步骤下分离非对映异构体的混合物。"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.
“对映异构体”指代彼此无重叠镜像的一种化合物的两个立体异构体。对映异构体的50:50的混合称为外消旋混合物或外消旋体,其在化学反应或处理过程中可以出现在已经没有立体选择性或立体定向性的情况下。"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.
“烷基”包括支链和直链饱和脂肪族烃基两者,并具有指定数量的碳原子数量,一般1至约12个碳原子。如在本文中使用的术语C
1-C
6烷基表示具有1至约6个碳原子的烷基。当本文中结合另一基团使用C
0-C
n烷基时,以(苯基)C
0-C
4烷基为例,指定的基团,在这种情况下,苯基是通过单个共价键(C
0)直接键合或通过具有指定的碳原子数(在这种情况下,1至约4个碳原子)的烷基链连接。烷基的实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、和仲戊基。
"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.
“烯基”指包括一个或多个不饱和的碳-碳键的直链和支链烃链,碳-碳键可以出现在沿着链的任一稳定点。本文中所述的烯基通常具有2至约12个碳原子。优选烯基是低级烯基,那些烯基具有2至约8个碳原子,如:C
2-C
8、C
2-C
6、和C
2-C
4烯基。烯基的实例包括乙烯基、丙烯基、和丁烯基。
"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.
“烷氧基”是指具有通过氧桥连接的指定数量的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、3-己氧基、和3-甲基戊氧基。"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.
卤素在本领域是公知的,优选F、Cl、Br、I。Halogens are well known in the art, F, Cl, Br, I are preferred.
术语“杂环”表示5-至8-元饱和环、部分不饱和环、或包含选自N、O和S的1至约4个杂原子且剩余的环原子是碳的芳族环,或是7至11元饱和环、部分不饱和环、或芳族杂环系统和10至15-元三环系统,该系统包含选自N、O和S的多环系统中的至少1个杂原子并且在多环系统中的各环中包含独立地选自N、O和S的至多约4个杂原子。除非另外指明,否则杂环可以连接至它在任何杂原子和碳原子处取代并且产生稳定结构的基团。当指明时,本文中所述的杂环可以在碳或氮原子上被取代,只要得到的化合物是稳定的。可以可选地季铵化杂环中的氮原子。优选杂环基中杂原子的总数不大于4而且优选杂环基中S和O 原子的总数不大于2,更优选不大于1。杂环基的实例包括:吡啶基、吲哚基、嘧啶基、哒嗪基(pyridizinyl)、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基(benz[b]thiophenyl)、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、二氢异吲哚基、5,6,7,8-四氢异喹啉、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡咯烷基、吗啉基、哌嗪基、哌啶基、和吡咯烷基。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.
“芳基或杂芳基”表示包含选自N、O和S的1至4个、或优选1至3个杂原子并且剩余环原子为碳的稳定的5-或6-元单环或多环。当杂芳基中S和O原子的总数超过1时,这些杂原子不彼此邻近。优选杂芳基中S和O原子的总数不大于2。尤其优选杂芳基中S和O原子的总数不大于1。可以可选地季铵化杂环中的氮原子。当指明时,这些杂芳基还可以用碳或非碳原子或基团取代。这种取代可以包括与可选地包含独立地选自N、O和S的1或2个杂原子的5至7-元饱和的环基的稠合,从而形成例如[1,3]二噁唑并[4,5-c]吡啶基。杂芳基的实例包括但不限于:吡啶基、吲哚基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。芳基优选苯基、萘基等。"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 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. Examples of 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.
“抑郁症”包括情绪低、活动兴趣下降、心理活动减缓或烦躁、食欲改变、注意力不集中或优柔寡断、过度内疚或自卑,并且在忧郁症、两极忧郁症、以及由于其它疾病或病况引起的情绪失常、物质引发的情绪失常和其他原因不明的情绪失常的情况下可能出现自杀意念,并且也可与各种其他精神性疾病(包括但不限于精神性失常、认知障碍、摄食障碍、焦虑症和人格障碍)共同存在。疾病的发展进程(longitudinal course)、病史、症状类型和病因有助于将情感性疾病的各种形式彼此区分开来。"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.
“化合物的盐”是所公开的化合物的衍生物,其中,母体化合物通过制备无毒的酸或其碱加成盐改性,并且还指这些化合物和这些盐的药用溶剂化物,包括水合物。药用盐的实例包括但不限于:碱性残基如胺类的无机或有机酸加成盐;酸性残基如羧酸的碱或有机加成盐;等等,以及包括一种或多种上述盐的组合。药用盐包括诸如从无毒无机或有机酸形成的母体化合物的无毒盐和季铵盐。例如, 无毒酸性盐包括衍生自无机酸的那些,例如:盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;其他可接受的无机盐包括金属盐如:钠盐、钾盐、铯盐等;碱土金属盐如:钙盐、镁盐等,以及包括一种或多种上述盐的组合。"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 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.
化合物的有机盐包括由诸如乙酸、三氟乙酸、丙酸、丁二酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、对氨基苯磺酸、2-乙酸基苯酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙磺酸、HOOC-(CH
2)
n-COOH(其中n为0至4)等的有机酸制备的盐;有机胺盐,如:三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N'-二苄基乙二胺盐等;和氨基酸盐,如:精氨酸盐、天冬氨酸盐、谷氨酸盐等,以及包括一种或多种上述盐的组合。
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.
图1不同剂量药物7天内的抗抑郁作用;Figure 1 Antidepressant effect of different doses of drugs within 7 days;
图2化合物C和D的抗抑郁作用;Figure 2 Antidepressant effects of compounds C and D;
图3化合物I5无敏华作用;Fig. 3 Compound I5 has no effect of allenhua;
图4化合物C有行为敏华作用;Figure 4 Compound C has the effect of acting as Minhua;
图5化合物D有行为敏华作用;Figure 5 Compound D has the effect of acting as Minhua;
图6I5对小鼠无位置偏爱作用;Figure 6I5 has no place preference effect on mice;
图7化合物C诱导位置偏爱;Figure 7 Compound C induces place preference;
图8化合物D诱导位置偏爱。Figure 8 Compound D induces place preference.
实施例1:(2R,6R)-6-羟基去甲基氯胺酮(HNK)的合成Example 1: Synthesis of (2R,6R)-6-hydroxydemethylketamine (HNK)
步骤一:在两口瓶或三口瓶,加入镁粉50克,引发后缓慢滴加溴代环戊烷119.2克与THF混合溶液,滴加完毕后,回流2-4h,制得1.6mol/L的环戊基格式试剂。THF和邻氯苯腈(50.0g)混合液加入840毫克CuBr,在冰浴条件下,滴加环戊基格式试剂(1.6mol/L,280ml)。滴加完毕后回流1h,冷却至室温,加入100ml水,然后加入200ml 15%稀硫酸溶液,搅拌过夜,旋干THF,用EA萃取,干燥,过硅胶柱,得到化合物A 2-氯苯基环戊基甲酮60g,产率80%。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%.
步骤二:按照已报道方法(Bioorganic&Medicinal Chemistry 2013,12,5098),将化合物A 20克(96mmol)溶于400毫升EA中,待溶解后加入溴化铜(54克,242mmol),升温回流3小时,然后冷却至室温,用硅藻土过滤固体不溶物,加二氯甲烷洗涤滤渣后与滤液合并浓缩,得到黄色的油状物化合物B 2-氯苯基(1-溴环戊基)甲酮。过硅胶柱得到化合物B纯品22克,产率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 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%.
步骤三:在200ml氨水中通入氨气直至饱和,加入化合物B(10g),搅拌24h,化合物C沉淀析出,过滤,干燥,得到棕色固体化合物C(7克)直接进行下一步,产率70%。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 %.
步骤四:将化合物C(5g)溶于干燥的THF,通入HCl气体至溶液pH为1,旋干溶液,得到固体盐酸盐。将固体盐酸盐加入单口烧瓶,在氮气保护下,置于190℃油浴中,约20min,冷却至室温,加入碳酸氢钠饱和溶液中和,用DCM萃取后,浓缩结晶得到化合物D去甲基氯胺酮HNK消旋体2.9克,产率75%。
1H NMR(400MHz,CDCl
3):δ7.67(dd,J=7.8,1.5Hz,1H),7.37–7.32(m,2H),7.25(m,1H),2.78–2.71(m,1H),2.61(m,1H),2.51–2.43(m,1H),2.08–2.0(m,1H),1.88–1.63(m,4H)。
Step 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).
步骤五:将化合物D(1.11克,5mmol)溶于2毫升甲醇,加入L-酒石酸(2.5mmol),搅拌1h,滴入到10毫升丙酮中,静至结晶,过滤得到L-酒石酸盐晶体。将得到L-酒石酸盐晶体继续重结晶3次后。晶体加入碳酸氢钠溶液中中和,用EA萃取,得到光学纯的化合物E(R)-去甲基氯胺酮165毫克,手性HPLC检测光学纯度为98.3%ee%,产率15%。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%.
手性HPLC检测步骤:将化合物E与对照的消旋体化合物D各1毫克溶解在1毫升乙醇中,置于安捷伦1260-A高效液相色谱仪上进行正相匀度分析,色谱柱Chiralcel-AD-H(4.6mm X 250mm),流动相A:(正己烷+0.1%二乙胺),流动相B:(乙醇+0.1%二乙胺),A:B=40:60,流速1mL/min。化合物E:R构型的异构体保留时间6.8min,对应的S构型的异构体保留时间5.3min。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.
步骤六:将化合物E(2.23g,10mmol)加入60ml THF中,加入三乙胺(2.7mL,20mmol)及Boc
2O(3.3g,15mmol),回流6h,冷却,旋干,过硅胶柱得到化合物F 2.92克,产率90%。
1H NMR(400MHz,CDCl
3):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,CDCl
3):δ207.9,152.3,134.5,132.6,130.3,130.0,128.3,125.2,78.0,66.1,38.5,37.4,29.7,27.2,20.9。
Step 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.
步骤七:将化合物F(2.91g,9mmol)加入到干燥的60ml THF中,在氩气保护下,冷却至-78℃,加入5毫升HMPA,然后慢慢滴加入2M的LDA的THF溶液(12ml,24mmol),搅拌30-40min,然后缓慢升温至-30℃搅拌1h,然后再冷却至-78℃并加入三甲基氯硅烷TMSCl(2.6g,24mmol),缓慢升温至-50℃,搅拌3h,倒入饱和氯化铵溶液并恢复至室温,浓缩溶剂THF并加EA萃取,有机相加无水Na
2SO
4干燥,旋干溶剂并真空干燥,得到的油状物加入100ml无水的DCM溶解,冷却至-15℃,在氩气保护下,加入mCPBA(2.5g,11mmol),搅拌1h后升温至室温,加入50ml DCM再搅拌1h,然后倒入饱和硫代硫酸钠和碳酸氢钠溶液(1:1),用DCM萃取,旋干溶剂并真空干燥,得到的油状物再加入 100mlTHF溶解,然后冷却至-5℃,加入四丁基氟化铵(3g,11.4mmol),搅拌30min,加入饱和NaHCO
3溶液,用EA萃取,旋干溶剂并真空干燥,过硅胶柱,得到化合物G 1.92g产率65%。
1H NMR(400MHz,CDCl
3):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,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 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.
步骤八:将化合物G(680mg)溶于5mL干燥的THF,室温下通入气体HCl至饱和并搅拌4h,加入20mL干燥的乙醚,有晶体析出,过滤得到化合物H(2R,6R)-6-羟基去甲基氯胺酮(HNK)的盐酸盐520mg,产率95%.
1H NMR(400MHz,CD
3OD):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)。
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).
实施例2:化合物I5的合成Example 2: Synthesis of Compound 15
将化合物G(170mg,0.5mmol)溶于3mL干燥THF,加入干燥三乙胺(0.28mL,2mmol),然后置冰浴条件下加入苯甲酰氯(117uL,1mmol),然后在1小时内慢慢升至室温,搅拌过夜,然后加入碳酸氢钠溶液,EA萃取,旋干溶剂并真空干燥,过硅胶柱,得到化合物H
4N-Boc-(2R,6R)-6-苯甲酰氧去甲基氯胺酮184mg,产率为85%.
1H NMR(400MHz,CDCl
3):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,CDCl
3):δ202.2,164.9,153.3,133.2,131.4,131.1,129.9,129.7,129.5,128.3,128.0,126.1,79.2,73.8,67.2,36.6,34.8,28.2,19.0
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 benzoyl chloride (117 uL, 1 mmol) was added under ice bath conditions, and then slowly over 1 hour Warm to room temperature, stir overnight, then add sodium bicarbonate solution, extract with EA, spin dry the solvent and vacuum dry, pass through a silica gel column to obtain compound H 4 N-Boc-(2R,6R)-6-benzoyloxynor Ketamine 184 mg, 85% yield. 1 H NMR (400 MHz, CDCl 3 ): δ 8.22-8.19 (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). 13 C NMR (100 MHz, CDCl 3 ): δ 202.2, 164.9, 153.3, 133.2, 131.4, 131.1, 129.9, 129.7, 129.5, 128.3, 128.0, 126.1, 79.2, 73.8 , 67.2, 36.6, 34.8, 28.2, 19.0
将化合物H
4(180mg)溶于3mL干燥的THF,室温下通入气体HCl至饱和并搅拌4h,加入15-20mL干燥的乙醚,有晶体析出,真空过滤得到化合物I
4(2R,6R)-6-苯甲酰氧去甲基氯胺酮盐酸盐128mg,产率83%.
1H NMR(400MHz,CD
3OD):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)
13C NMR(100 MHz,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.
Compound H 4 (180 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 obtained to obtain compound I 4 (2R, 6R)- 6-Benzoyloxydesmethylketamine hydrochloride 128 mg, 83% yield. 1 H NMR (400 MHz, CD 3 OD): δ 9.25-9.20 (brs, 3H), 8.21-8.19 (m, 2H) 13 C NMR (100 MHz, 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.
将化合物H(339mg,1mmol)溶于8mL干燥THF,加入干燥三乙胺(0.56mL,4mmol),然后加入对二甲氨基苯甲酰氯(275mg,1.5mmol),回流过夜,旋干溶剂,然后加入碳酸氢钠溶液,EA萃取分液,有机相旋干溶剂并真空干燥,过硅胶柱得到化合物H
5N-Boc-(2R,6R)-6-对二甲氨基苯甲酰氧去甲基氯胺酮292mg,产率60%.将化合物H
5(292mg)溶于6mL干燥的THF,室温下通入气体HCl至饱和并搅拌4h,加入15-20mL干燥的乙醚,有晶体析出,真空过滤得到化合物I
5(2R,6R)-6-对二甲氨基苯甲酰氧去甲基氯胺酮双盐酸盐148mg,产率54%.化合物I
5
1H NMR(400MHz,CD
3OD):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).
13C 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.
Compound H (339 mg, 1 mmol) was dissolved in 8 mL of dry THF, dry triethylamine (0.56 mL, 4 mmol) was added, then p-dimethylaminobenzoyl chloride (275 mg, 1.5 mmol) was added, refluxed overnight, the solvent was spin-dried, and then Sodium bicarbonate solution was added, EA was extracted and separated, the organic phase was spin-dried to dry the solvent and dried in vacuo, passed through a silica gel column to obtain compound H 5 N-Boc-(2R, 6R)-6-p-dimethylaminobenzoyloxydemethyl Ketamine 292 mg, yield 60%. Compound H 5 (292 mg) was dissolved in 6 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 the compound was obtained by vacuum filtration I 5 (2R,6R)-6-p-dimethylaminobenzoyloxydesmethylketamine dihydrochloride 148 mg, yield 54%. Compound I 5 1 H NMR (400 MHz, CD 3 OD): δ 8.00 (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): δ 200.8, 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.
实施例3:化合物C和D的合成Example 3: Synthesis of Compounds C and D
通过如下制备方法,制备获得了化合物C和D。Compounds C and D were prepared by the following preparation methods.
实施例4:活性测试:Example 4: Activity test:
1.强迫游泳实验1. Forced swimming experiment
在强迫游泳试验(FST)之前1小时,将小鼠转移到实验室。该测试是在正常光线条件下进行的,并由数字摄像机监控。在测试过程中,将小鼠分别放入装有20厘米水(23±1℃)的透明玻璃圆筒(高28.5厘米,直径14厘米)中。在第一天,训练小鼠6分钟,然后从圆柱体中移出。第二天,小鼠给予saline,HNK,I5,C,D后不同时间间隔后测试其不懂时间。在整个6分钟的游泳测试的最后4分钟内,通过Noldus系统的EthoVision XT(Noldus,荷兰)记录了静止时间,该时间定义为被动漂浮,除了使动物的头部保持在水上所必需的动作之外,没有其他运动。每两到三次试验后,更换瓶中的水。游泳测试后,将小鼠从水中移出并在红外灯下干燥。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. 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.
小鼠灌胃分别给予1mg(A),10mg(B)和30mg(C)的HNK,I5并在1小时和7天后测量其不动时间。不动时间的百分比表示为平均值±SEM。*p <0.05,**p<0.01,与基础测试相比。每组N=8。saline,盐水组;I5,I5处理组;HNK:2R,6R-羟基去甲酮胺处理组。Mice were given 1 mg (A), 10 mg (B) and 30 mg (C) of HNK, I5 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; I5, I5 treatment group; HNK: 2R, 6R-hydroxynorketamine treatment group.
2.成瘾性研究2. Addiction Research
材料和方法Materials and Method
动物:8-12周C57BL/6J雄性小鼠随机分组,每组10只,体重18-22克,室温(22±1℃)饲养,湿度(50±10)%,光照时间8:00-20:00,小鼠自由摄食饮水,在实验前至少适应实验环境2~3d。所有实验均在8:00~16:00进行。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.
行为敏化实验:Behavioral Sensitization Experiment:
1.1小动物自主活动测定:动物自发活动红外分析系统,由自发活动箱、红外探头装置及数据采集系统构成。自发活动箱尺寸为40cmX 40cm X 65cm,隔音隔光,具有通风装置。由红外探头记录动物活动状况,计算动物的自发活动次数。为测试药物对小鼠自发活动的影响,小鼠随机分4组,每组10只。分组:vehicle,I5,C,D(5.0、10.0、30.0mg/kg)、mor(10mg/kg)。每日上午分别灌胃1次,连续7d;其后停药7d(无任何处理)。第15天每组小鼠灌胃给予Veh、药物(5.0、10.0、30.0mg/kg)激发。d1、d7、d15给药后立即测定1h内小鼠的自发活动。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 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. 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, I5, 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实验:三室CPP系统包括左右黑白箱(25cmx25cmx30cm)由中间箱隔开(10cmx25cmx30cm),实验时小鼠从中间箱放入,并可以自由穿梭至黑、白两箱。黑白两箱与中间箱之间各有穿梭门一个,大小为5cmx5cm。实验采用偏性程序,分为预测试、训练、测试3个阶段,在整个实验过程中保证箱内光线、色调、气味等环境条件的一致。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.
预测试:d1-3,将箱内隔板打开,所有小鼠皮下注射盐水后放入中间箱,让其在箱中自由活动15min,每天1次,连续3d。记录小鼠分别在黑白箱中的停留时间,确定小鼠的天然偏爱倾向;以非天然偏爱箱为伴药箱训练小鼠。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.
训练期:d4-9,关闭穿梭门,小鼠随机分组,包括Veh,mor,I5,C,D(5.0、10.0、30.0mg/kg)、mor(10mg/kg),每组10只。单数日上午所有小鼠先灌胃给予生理盐水,立即放入非伴药箱(黑箱)中45min;单数日下午分别灌胃给予Veh,mor,I5,C,D(5.0、10.0、30.0mg/kg),其后立即放入伴药 箱(白箱)中45min。双数日的训练顺序相反。上下午训练间隔大于6h,且每天的训练时间固定,连续训练6d,每组10只。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. In the morning of odd-numbered days, 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.
测试期:d10拿掉隔板,将小鼠放入中间箱,让其自由跑动,同时记录15min内小鼠在白箱中停留时间。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.
统计学分析:实验数据以X±SEM表示。采用graphpad软件进行统计分析,两组比较采用t检验;多组间比较采用one-way ANOVA分析,然后用LSD法两两比较。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.位置性偏爱实验3. Positional Preference Experiment
位置性偏爱通过三室系统测试,以非天然偏爱箱为伴药箱训练小鼠,训练期小鼠分别给予生理盐水(Veh),吗啡(mor,10mg/kg),I5、C和D(5.0、10.0、30.0mg/kg),连续训练6天后测试,记录15min内小鼠在白箱中停留时间。与Veh组比较,*P<0.05(n=10)。Positional preference was tested by a three-chamber system. Mice were trained with a non-natural preference box as the companion medicine box. During the training period, the mice were given saline (Veh), morphine (mor, 10 mg/kg), I5, 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.
实施例5:实验结果Example 5: Experimental Results
1.小鼠抑郁样行为测试结果:1. Test results of depressive-like behavior in mice:
1mgHNK、I5均无抗抑郁作用;10mgHNK、I5均有抗抑郁作用,I5有长效作用,药效7天基本无衰减,而HKN7天内药效衰减很快,第7天基本无药效。30mgHNK、I5均有抗抑郁作用,I5有长效作用,药效7天基本无衰减,而HKN7天内药效衰减很快,第7天基本无药效。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.
化合物C和D在30mg时并无抗抑郁效果。Compounds C and D had no antidepressant effect at 30 mg.
与HNK处理组相比,I5处理组在给药7天后仍有显著的抗抑郁效果,表现为动物在强迫游泳时的不动时间降低。I5组的不动时间更少。10mg和30mg处理组之间没有显著差别,虽然30mg组呈现更强的降低趋势。化合物C,D均无抗抑郁效果。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.
2.成瘾性实验2. Addiction Experiment
不同剂量(5mg,10mg,30mg)I5对小鼠无行为敏华作用。Different doses (5mg, 10mg, 30mg) of I5 had no effect on the behavior of mice.
不同剂量(5mg,10mg,30mg)C和D对小鼠有行为敏华作用。Different doses (5mg, 10mg, 30mg) of C and D have behavioral Minhua effect on mice.
3.位置性偏爱实验3. Positional Preference Experiment
不同剂量(5mg,10mg,30mg)I5对小鼠无位置偏爱性作用。Different doses (5mg, 10mg, 30mg) of I5 had no place preference effect on mice.
不同剂量(5mg,10mg,30mg)C和D诱导小鼠位置偏爱性。Different doses (5 mg, 10 mg, 30 mg) of C and D induced place preference in mice.
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。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.
以上所述实施例仅表达了本申请的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对申请专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本申请构思的前提下,还可以做出若干变形和改进,这些都属于本申请的保护范围。因此,本申请专利的保护范围应以所附权利要求为准。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 a limitation on the scope of the patent application. It should be pointed out 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 (13)
- 一种化合物、化合物的盐、立体异构体、或互变异构体在制备预防或治疗麻醉、镇痛、改善认知功能、肺保护、抗抑郁、改善焦虑和创伤后应激综合症、肌萎缩侧索硬化症或,复杂性区域疼痛综合症药物中的应用,所述化合物具有式I所示结构: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:其中:in:其中m为0-3的整数,n为0-4的整数;Where m is an integer from 0 to 3, and n is an integer from 0 to 4;R 1和R 2各自独立地选自H、卤素、羟基、氨基、氰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10杂环基、取代或未取代的C 1-C 6烷氧基、取代或未取代的单-和二-C 1-C 6烷基氨基、取代或未取代的芳基、取代或未取代的杂芳基中的1种或多种; 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为卤素; R 3 is halogen;R 4选自H、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 8酰基、取代或未取代的芳基酰基或取代或未取代的杂芳基酰基; 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选自取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10杂环基、取代或未取代的芳基、取代或未取代的杂芳基; 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和R 7各自独立地选自H、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 2-C 10杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的C 1-C 8酰基、取代或未取代的芳基酰基或取代或未取代的杂芳基酰基; 或者R 6和R 7与其所连的N原子一起形成取代或未取代的3-10元单环或双环结构; 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; 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 structure;所述取代是指被OH;NH 2;C 1-C 10烷基、烯基或炔基;C 1-C 10烷基胺基;巯基;C 1-C 10烷基巯基;C 1-C 20烷氧基;C 1-C 10羰基;C 3-C 10环烷基;具有选自N、S、O、P中一个多个杂原子的3-10元杂环基;C 6-C 20芳基;C 2-C 20杂芳基;硝基氰基、或卤素取代。 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.
- 如权利要求1-7之一所述的应用,所述药物还包含药学上可接受的载体。The use of any one of claims 1-7, wherein the medicament further comprises a pharmaceutically acceptable carrier.
- 如权利要求8所述的应用,所述药物还包含药学上可接受的载体。The use of claim 8, wherein the medicament further comprises a pharmaceutically acceptable carrier.
- 如权利要求1-7之一所述的应用,其中所述疼痛包括:慢性疼痛或神经性疼痛;抑郁症包括:两极忧郁症、重度抑郁症;改善焦虑和创伤后应激综合症;改善认知功能包括预防或治疗阿尔茨海默尔痴呆、帕金森。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.
- 如权利要求8所述的应用,其中所述疼痛包括:慢性疼痛或神经性疼痛;抑郁症包括:两极忧郁症、重度抑郁症;改善焦虑和创伤后应激综合症;改善认知功能包括预防或治疗阿尔茨海默尔痴呆、帕金森。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.
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