阅读说明：本技术 一种长效化合物 (Long-acting compound ) 是由 周强 叶涛 李书鹏 于 2019-06-18 设计创作，主要内容包括：本申请提供了一种具有长效治疗效果的化合物,其可以用于制备抗抑郁、麻醉、镇痛、改善认知功能、肺保护、肌萎缩侧索硬化症或复杂性区域疼痛综合症药物。(the application provides a compound with long-acting therapeutic effect, which can be used for preparing medicaments for resisting depression, anesthesia, analgesia, improving cognitive function, protecting lungs, amyotrophic lateral sclerosis or complex regional pain syndrome.)

1. a compound of the formula:

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

R1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

R3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

2. A compound of the formula:

wherein

R3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl, C6-C10 aryl or mono-or poly-cyclic heteroaryl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

3. A compound of the formula:

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

R1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

R3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

4. A compound of the formula:

Wherein

R3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl, C6-C10 aryl or mono-or poly-cyclic heteroaryl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

Or a salt, stereoisomer, tautomer of the foregoing compound.

5. the compound according to any one of claims 1 to 4, characterized by being the following:

6. the compound according to any one of claims 1 to 4, characterized by being the following:

7. A compound of the formula:

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

R1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

r5 and R6 are protecting groups;

Or a salt, stereoisomer, tautomer of the foregoing compound.

8. A compound of the formula:

Wherein R5 and R6 are H or a protecting group;

or a salt, stereoisomer, tautomer of the foregoing compound.

9. a compound represented by:

10. A compound represented by:

11. A pharmaceutical composition characterized by comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. the pharmaceutical composition of claim 11, wherein: the carrier includes excipients and diluents.

13. The pharmaceutical composition of claim 11, wherein: the carrier is one or more of a binder, a buffer, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a glidant, a lubricant, a preservative, a stabilizer, a surfactant, a tableting agent, and a wetting agent.

14. the pharmaceutical composition of claim 13, wherein: the carrier is one or more of sugar, starch, cellulose, malt, gelatin, talc and vegetable oil.

Technical Field

the present application relates to the field of medicine, and in particular to a compound for the treatment of depression, neuropathic and chronic pain, including Complex Regional Pain Syndrome (CRPS).

Background

ketamine (ketamine) is a representative of the phencyclidine intravenous anesthetic commonly used in clinic, and is one of the anesthetics with rapid development of clinical and basic research in recent years. In clinical practice, it is often used to meet the anesthesia needs of pediatric, obstetric, perioperative and patients with specific diseases because of its rapid induction, short duration of action, rapid recovery, and minimal impact on the respiratory and circulatory systems.

Ketamine was first synthesized in 1962, was used in humans in 1965, and was officially approved by the FDA for clinical use in 1970. Its typical "split anesthesia" and short-term, definitive analgesia makes it ever red for the best, but subsequent discovery of psychiatric side effects and rapid development of other intravenous anesthetic drugs has led to a substantial reduction in the clinical use of ketamine. In the last 10 years, with the research on the usage amount of ketamine and the discovery of the anti-inflammatory, antidepressant, neuroprotection, analgesic and other effects, the medical community has a rising interest in ketamine.

in the past, ketamine has the functions of strongly relieving pain and forgetting, simultaneously keeping spontaneous respiration and airway protective reflex, keeping hemodynamics stable and the like, so that the effect of ketamine in the pre-hospital anesthesia analgesia is not negligible. Ketamine has both neurotoxic and neuroprotective effects, a huge surgical stimulus theoretically may balance the anesthetic injury, and ketamine can alleviate the neurocognitive function impairment caused by surgical injury stimuli, and whether ketamine alone causes neuroprotection or neuroimpairment is directly related to the dose of ketamine used.

ketamine has an effect on post-operative cognitive function. After 50 patients receiving ketamine anesthesia are tested by researchers, the ketamine general anesthesia can reduce the cognitive function of the patients after 6 hours of operation, but has no influence on the cognitive function of the patients after 24 hours of operation. Hudetz et al found that the administration of 0.5mg/kg ketamine at the time of general anesthesia induction reduced the incidence of post-operative cognitive dysfunction for 1 week after cardiac surgery, which may be related to the anti-inflammatory effects of ketamine. In recent years, numerous clinical trials have demonstrated that the application of ketamine in a single small intraoperative dose can reduce the incidence of postoperative post-operative cognitive dysfunction (POCD).

Ketamine has analgesic effect. Sub-anesthetic doses of ketamine are often used for anti-hyperalgesia, and the treatment of acute and chronic pain. Research proves that the ketamine saline mixed solution before anesthesia induction can obviously reduce the incidence and severity of postoperative pharyngalgia caused by general anesthesia tracheal intubation. The use of opioids during surgery increases the amount of opioid analgesic used after surgery, an effect called opioid tolerance. The clinical findings show that the use of ketamine can prevent opioid tolerance, reverse morphine tolerance and enhance morphine analgesic effect. Studies have also demonstrated that application in small dose ketamine surgery can prevent remifentanil-induced postoperative hyperalgesia. Cagla and the like find that ketamine is injected into a knee arthroscopic surgery patient for 0.15mg/kg of postoperative intravenous injection, the ketamine can obviously improve postoperative analgesic satisfaction, and the sedation score is lower than that of a ketamine compound midazolam group.

Ketamine has a lung protective effect. In recent years, ketamine has been found to have a significant lung protective effect. Clinical experiments prove that the level of inflammatory factors in blood can be reduced by veins and atomization before single lung ventilation in the thoracic surgery, the atomization inhalation is more beneficial to a cardiovascular system and airway pressure, and the atomization effect of the lung ventilation side is superior to that of double-lung atomization. Ketamine is also commonly used in the clinic for the rescue of fatal asthma attacks where conventional therapy is ineffective, and its use is well recognized as improving prognosis.

ketamine has antidepressant effect. Berman et al first reported in 2000 that more than 50% of patients scored a reduction in the Hamilton depression scale by more than 50% within 72h after a single intravenous injection of a sub-anesthetic dose of ketamine (0.5mg/kg, more than 40min intravenous injection) (see, for example, Berman RM, Capphiello A, and A, et al, anti effects of ketamine in suppressed patients [ J ]. Biol Psychiatry, 2000, 47 (4): 351-354). PaulR et al found that S-ketamine had similar antidepressant effects but less psychologically side effects than racemic ketamine (see: Paul R, Schaaff N, Padberg F, et al. comparative of scientific ketamine and S-ketamine in vitro therapeutic major expression: report of two cases [ J ]. World J diol kinase, 2009,10(3): 241-244). In recent years, more animal and clinical studies have further demonstrated the antidepressant effect of ketamine. Ketamine is also used in anesthesia for the treatment of electrical shock in depressed patients. In 2012, the U.S. department of government health and human services, cooper health system and stanford research institute filed patent applications with application number CN 201280062294X entitled (2R,6R) -hydroxynorketamine, (S) -dehydronorketamine and other stereoisomeric dehydro-and hydroxylated metabolites of (R, S) -ketamine for the treatment of depression and neuropathic pain. CNS (central nervous system) side effects are related to the activity of (R, S) -ketamine on NMDA receptors, in which application (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) was studied and synthesized on the basis of ketamine, which compound is inactive on NMDA receptors, thus avoiding possible side effects, and which compound is said to have an effect on the treatment of bipolar depression, major depression, Alzheimer' S dementia, amyotrophic lateral sclerosis, Complex Regional Pain Syndrome (CRPS), chronic pain, or neuropathic pain.

In animal experiments, we found that (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) has a short duration of drug effect after administration, i.e., the effect is lost within 1 week, which severely limits the desired long-lasting effect in the treatment of depression. Therefore, the structural modification of (2R, 6R; 2S,6S) -Hydroxynorketamine (HNK) to obtain a drug with longer drug effect has great treatment potential.

Disclosure of Invention

The present application relates to a compound having antidepressant, anesthetic, analgesic, cognitive function improving, pulmonary protection, prevention or treatment of amyotrophic lateral sclerosis or prevention or treatment of complex regional pain syndrome.

Compared with the existing known HNK compounds, the compound has longer drug effect time, specifically shows that HNK is metabolized within one week and loses curative effect, and the drug effect time of the compound can last for more than 1 week.

The present application provides compounds of the formula:

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

R1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

r2 is independently selected from

R3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

the present application provides compounds of the formula:

Wherein

r3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl, C6-C10 aryl or mono-or poly-cyclic heteroaryl;

r4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

the present application provides compounds as shown below:

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

r1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

r3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl;

r4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

the present application provides compounds of the formula:

Wherein

r3 is independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 acyl, C6-C10 aryl or mono-or poly-cyclic heteroaryl;

R4 is independently selected from C1-C8 acyl, arylacyl, or heteroarylacyl;

or a salt, stereoisomer, tautomer of the foregoing compound.

The compound as described above, characterized by being the following compound:

the compound as described above, characterized by being the following compound:

The preparation method of the compound is characterized by comprising the following steps:

use of any of the compounds as described above for the manufacture of a medicament for anaesthesia, analgesia, cognitive function improvement, lung protection, antidepressant, amyotrophic lateral sclerosis, complex regional pain syndrome.

Wherein the pain comprises: chronic pain or neuropathic pain; depression includes: bipolar depression, severe depression, depression associated with neurodegenerative diseases; improving cognitive function includes preventing or treating alzheimer's dementia, parkinson's disease, and the like.

All of the above diseases, either prophylactic or therapeutic, are also contemplated.

The present application also provides intermediate compounds represented by the formula:

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

r1 and R2 are independently selected from 1 or more of H, halogen, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, mono-and di-C1-C4 alkylamino, C1-C2 haloalkyl, C1-C2 haloalkoxy, C6-C10 aryl, or monocyclic or polycyclic heteroaryl;

R5 and R6 are protecting groups;

Or a salt, stereoisomer, tautomer of the foregoing compound.

the present application also provides intermediate compounds represented by the formula:

Wherein R5 and R6 are H or a protecting group;

Or a salt, stereoisomer, tautomer of the foregoing compound.

The present application also provides intermediate compounds represented by the formula:

the present application also provides intermediate compounds represented by the formula:

Stereoisomers of all the above compounds include enantiomers, diastereomers.

Where all of the above compounds exist in different tautomeric forms, the invention is not limited to any one particular tautomer, but includes all tautomeric forms.

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

the present application also provides a pharmaceutical composition, and the compounds disclosed herein can be administered as pure chemicals, but preferably as a pharmaceutical composition. Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt in combination with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may comprise the compound or salt as the only active agent, but preferably comprises at least one other active agent. In certain embodiments, the pharmaceutical composition is an oral dosage form comprising from about 0.1mg to about 1000mg, from about 1mg to about 500mg, or from about 10mg to about 200mg of a compound of formula I, and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of another active agent in a unit dosage form.

The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by buccal administration, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers. The pharmaceutical composition may be formulated in any pharmaceutical form, such as: aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit forms containing appropriate quantities of the active component, such as an effective amount to achieve the desired purpose.

carriers include excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient to be treated. The carrier may be inert or it may itself have a pharmaceutical benefit.

Types of vectors include, but are not limited to: binders, buffering agents, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some vectors may be listed in more than one category, such as: vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder (powdered tragacanth), malt, gelatin, talc and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially affect the biological function of the compounds of the invention.

the compounds or salts 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 may be administered in conjunction with another active agent selected from any one of the following:

Antidepressants: escitalopram oxalate, feloxetine, paroxetine, duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine, naltrexone, mirtazapine, venlafaxine, atorvastatin, bupropion, doxepin, amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole, clozapine, closerpine, olanzapine, quetiapine, risperidone, ziprasidone, carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, donepezil, galantamine, memantine, rivastigmine, homotaurine (tramiprosate), or pharmaceutically active salts or prodrugs thereof, or combinations of the above;

schizophrenia drug: aripiprazole, lurasidone, asenapine, clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine, olanzapine, closerpine, flupentixol (flupenttioxol), phenoxazine, haloperidol, chlorpromazine, fluphenazine, paliperidone;

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

ALS drugs: riluzole;

Pain medication: acetaminophen, aspirin, NSAIDS, including: diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetinopodies, Cox-2 inhibitors such as celecoxib, and narcotic pain medications such as: buprenorphine, butorphanol, codeine, dihydrocodeinone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, analgesin, propoxyphene, central analgesic tramadol.

the foregoing list of other active agents is exemplary and not comprehensive. Other active agents not included in the above list may be administered in conjunction with the compound of formula I. Although in some embodiments, the other active agent will be administered at a dose less than the generally prescribed dose and in some cases less than the minimum approved dose, the other active agent may be administered according to its approved regulatory information.

the disclosure includes methods of treating depression, particularly bipolar depression and major depression, particularly treatment refractory depression (treatment-refractory depression), wherein an effective amount of the compound is the lowest dose effective to alleviate the symptoms of depression, wherein the alleviation of the symptoms of depression is by a 50% or more reduction in the rating scale score for depression symptoms, or a score of less than or equal to 7 on HRSD17, or a score of less than or equal to 5 on QID-SR16, or a score of less than or equal to 10 on MADRS.

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

The terminology convention:

"stereoisomers" are compounds having the same chemical composition but differing in the arrangement of atoms or groups in space.

"diastereoisomers" are stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example: melting point, boiling point, spectral characteristics and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis, crystallization, using, for example, chiral HPLC columns in the presence of resolving agents or chromatography.

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

"alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C1-C6 alkyl as used herein denotes an alkyl group having from 1 to about 6 carbon atoms. When C0-Cn alkyl is used herein in connection with another group, exemplified by (phenyl) C0-C4 alkyl, the indicated group, in this case, phenyl is bonded directly by a single covalent bond (C0) or attached by an alkyl chain having the indicated number of carbon atoms (in this case, 1 to about 4 carbon atoms). Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.

"alkenyl" refers to straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, such as: C2-C8, C2-C6, and C2-C4 alkenyl. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.

"alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.

The term "heterocycle" means a 5-to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing from 1 to about 4 heteroatoms selected from N, O and S with the remaining ring atoms being carbon, or a 7-to 11-membered saturated ring, a partially unsaturated ring, or an aromatic heterocyclic system and a 10-to 15-membered tricyclic ring system containing at least 1 heteroatom in a polycyclic ring system selected from N, O and S and containing up to about 4 heteroatoms independently selected from N, O and S in each ring in the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that it is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on carbon or nitrogen atoms, as long as the resulting compounds are stable. The nitrogen atoms in the heterocycle may optionally be quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not more than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidyl, pyridazinyl (pyridizinyl), pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl (benz [ b ] thiophenyl), isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7, 8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazoyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.

"aryl or heteroaryl" means a stable 5-or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S and the remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl group is not greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. The nitrogen atoms in the heterocyclic ring may optionally be quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 5 to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S, thereby forming, for example, a [1,3] dioxazolo [4,5-c ] pyridyl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7, 8-tetrahydroisoquinoline.

"depression" includes low mood, decreased activity interest, reduced or irritated psychological activity, altered appetite, poor or mild attention, excessive guilt or self-mutilation, and suicidal ideation may occur in cases of depression, bipolar depression, and mood disorders due to other diseases or conditions, substance-induced mood disorders, and other unexplained mood disorders, and may also co-exist with various other psychiatric disorders (including but not limited to psychiatric disorders, cognitive disorders, feeding disorders, anxiety disorders, and personality disorders). The progression of the disease (longitudinal course), history, type of symptoms and etiology help to distinguish the various forms of affective disease from one another.

"salts of compounds" are derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base addition salts thereof, and also refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; base or organic addition salts of acidic residues such as carboxylic acids; and the like, as well as combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable salts include non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non-toxic acidic salts include those derived from inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; other acceptable inorganic salts include metal salts such as: sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as: calcium salts, magnesium salts, and the like, as well as combinations comprising one or more of the foregoing salts.

Organic salts of the compounds include salts prepared from organic acids 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH2) n-COOH (where n is 0 to 4), and the like; organic amine salts, such as: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, and the like; and amino acid salts, such as: arginine salts, aspartic acid salts, glutamic acid salts, and the like, as well as combinations comprising one or more of the foregoing salts.

Drawings

FIG. 1 results of a mouse Depression-like behavior test;

FIG. 2 differential protein analysis;

FIG. 3 enrichment analysis of biological processes and molecular functions of differential proteins;

FIG. 4 enrichment analysis of the signaling pathway of differentially expressed proteins;

FIG. 5-NMR spectra of the compounds of FIG. 10.

Detailed Description