WO2022022651A1 - 一种预防和治疗精神障碍性疾病的化合物及其应用 - Google Patents

一种预防和治疗精神障碍性疾病的化合物及其应用 Download PDF

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WO2022022651A1
WO2022022651A1 PCT/CN2021/109365 CN2021109365W WO2022022651A1 WO 2022022651 A1 WO2022022651 A1 WO 2022022651A1 CN 2021109365 W CN2021109365 W CN 2021109365W WO 2022022651 A1 WO2022022651 A1 WO 2022022651A1
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compound
pharmaceutical composition
trek
depression
ion channel
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PCT/CN2021/109365
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English (en)
French (fr)
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阳怀宇
李扬
郭飞
蒋华良
张乾森
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中国科学院上海药物研究所
绍兴从零医药科技有限公司
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Priority to EP21850238.3A priority Critical patent/EP4190322A4/en
Priority to US18/018,290 priority patent/US20230301947A1/en
Priority to CN202180058434.5A priority patent/CN116194093A/zh
Priority to JP2023507254A priority patent/JP2023536590A/ja
Publication of WO2022022651A1 publication Critical patent/WO2022022651A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicinal chemistry, more particularly to a compound for preventing and treating mental disorders and its application.
  • Depression is a common mood disorder that can cause suicidal thoughts and behaviors in severe cases, affecting 16% of the population at some point in their lives. Depression is a serious mental disorder characterized by high prevalence, high recurrence rate, high disability rate and high suicide rate. Depression not only seriously affects the physical and mental health of patients, but also brings a lot of economic burden. From a comprehensive analysis of clinical diagnostics, pathological mechanisms and treatment outcomes, depressive disorder is a very complex psychiatric disorder.
  • Major depressive disorder is a serious mental disorder with generally low recovery rates and high relapse rates, with a chronic disease rate of about 20%.
  • the global annual cost of major depression is about $83 billion, which mainly includes indirect costs caused by the decline of psychosocial functioning (especially labor performance).
  • Treatment-resistant depression arises from the goals of treatment for MDD. Broadly speaking, the primary goal of treating MDD is to bring affected individuals to a state of full recovery from clinically significant symptoms and/or dysfunction (eg, in work, personal, and family life). Clinically, TRD is defined as failure to achieve remission with two or more appropriate antidepressants.
  • the main targets of antidepressants are monoamine receptors and transporters.
  • these clinical first-line drugs have the disadvantages of slow onset, large individual differences, and ineffectiveness in 30% of patients.
  • the purpose of the present invention is to provide a novel drug for treating or preventing mental disorders (eg, depression).
  • mental disorders eg, depression
  • a compound of formula I or a pharmaceutically acceptable salt thereof characterized in that it is used for (i) preparing a medicament for preventing and/or treating TREK-1 ion channel related diseases A composition or preparation, (ii) preparing a pharmaceutical composition or preparation for preventing and/or treating mental disorders and/or (iii) preparing a TREK-1 ion channel inhibitor;
  • the compound of formula I is compound CLA096, namely N-benzyl-2-(N-(4-chlorophenyl)methanesulfonylamino)-N-methylacetamide.
  • the TREK-1 ion channel-related disease refers to a disease that can be treated, prevented or ameliorated by inhibiting the TREK-1 ion channel.
  • the TREK-1 ion channel-related diseases include mental disorders.
  • the mental disorders include: depression, anxiety, schizophrenia, bipolar disorder, or a combination thereof.
  • the TREK-1 ion channel-related diseases include: depression, anxiety, schizophrenia, bipolar disorder, or a combination thereof.
  • the depression includes: major depression and/or treatment-resistant depression.
  • the prevention and/or treatment of TREK-1 ion channel-related diseases includes: anti-depression, anti-anxiety, anti-schizophrenia, anti-bipolar disorder, or a combination thereof.
  • the prevention and/or treatment of mental disorders includes: anti-depression, anti-anxiety, anti-schizophrenia, anti-bipolar disorder, or a combination thereof.
  • the pharmaceutical composition further comprises one or more additional active ingredients selected from the group consisting of:
  • the additional active ingredient is not the compound of formula I and its pharmaceutically acceptable salts.
  • the drugs for treating or preventing mental disorders include active ingredients for treating depression or antidepressant drugs.
  • the pharmaceutical composition further contains other active ingredients for treating depression.
  • the administration dose of the compound of formula I is 0.1-50 mg/kg body weight, preferably 1-5 mg/kg body weight.
  • the adverse reactions include: significant changes in body weight and death.
  • the pharmaceutical composition contains 0.001-99 wt % of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition contains 0.1-90 wt %, preferably 1-80 wt % of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
  • the dosage form of the pharmaceutical composition includes oral dosage form, injection and/or inhalation dosage form.
  • the oral dosage form includes: tablet, capsule, film, and/or granule.
  • the oral dosage form is a sustained-release dosage form or a non-sustained-release dosage form.
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises one or more additional active ingredients selected from the group consisting of:
  • the additional active ingredient is not the compound of formula I and its pharmaceutically acceptable salts.
  • the drugs for treating or preventing mental disorders include active ingredients for treating depression or antidepressant drugs.
  • the pharmaceutical composition further comprises other active ingredients for treating depression or antidepressant drugs.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the total content of the compound of formula I or its pharmaceutically acceptable salt is 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% of the pharmaceutical composition %.
  • the pharmaceutical composition is used to prevent and/or treat TREK-1 ion channel related diseases.
  • the pharmaceutical composition is used to prevent and/or treat mental disorders.
  • the TREK-1 ion channel-related diseases include mental disorders.
  • the mental disorders include: depression (including major depressive disorder and/or treatment-resistant depression), anxiety disorder, schizophrenia, bipolar disorder, or a combination thereof.
  • the pharmaceutical composition is used for the prevention and/or treatment of major depressive disorder.
  • the pharmaceutical composition is used for the prevention and/or treatment of treatment-resistant depression.
  • a kind of TREK-1 ion channel inhibitor is provided, and described inhibitor comprises compound as shown in formula I or its pharmaceutically acceptable salt:
  • a method for preventing and/or treating TREK-1 ion channel-related diseases comprising the steps of: administering a compound of formula I or a pharmaceutically acceptable salt thereof to an object in need; wherein, the The compounds of formula I are as defined in the first aspect.
  • the TREK-1 ion channel-related disease is a mental disorder.
  • the mental disorders include: depression, anxiety, schizophrenia, bipolar disorder, or a combination thereof.
  • the TREK-1 ion channel-related diseases include: depression, anxiety, schizophrenia, bipolar disorder, or a combination thereof.
  • the subject includes: a human, or a non-human mammal.
  • the non-human mammals include: primates, or rodents (such as mice, rats, etc.).
  • the administered dose is 1-20 mg/kg body weight, preferably 5 mg/kg body weight.
  • the frequency of administration is 1-4 times/day, preferably 1 time/day.
  • the total daily dose of the administration is 1-20 mg/kg body weight, preferably 5 mg/kg body weight.
  • the administration time ranges from 2 weeks to 5 years, preferably from 2 months to 1 year.
  • a method for preventing and/or treating mental disorders comprising the steps of: administering a compound of formula I or a pharmaceutically acceptable salt thereof to an object in need; wherein, the formula I Compounds are as defined in the first aspect.
  • the mental disorders include: depression, anxiety, schizophrenia, bipolar disorder, or a combination thereof.
  • the mental disorder is depression.
  • the subject includes: a human, or a non-human mammal.
  • the non-human mammals include: primates, or rodents (such as mice, rats, etc.).
  • the administered dose is 1-20 mg/kg body weight, preferably 5 mg/kg body weight.
  • the frequency of administration is 1-4 times/day, preferably 1 time/day.
  • the total daily dose of the administration is 1-20 mg/kg body weight, preferably 5 mg/kg body weight.
  • the administration time ranges from 2 weeks to 5 years, preferably from 2 months to 1 year.
  • a medicine kit is provided, and the medicine box includes:
  • the indications of the kit described in the description include: mental disorders; preferably, the indications include: depression (major depression and/or treatment-resistant depression) , anxiety, schizophrenia, and/or bipolar disorder.
  • the dosage of the drug or preparation for administration is 1-20 mg/kg body weight, preferably 5 mg/kg body weight, based on the active ingredient.
  • the administration frequency of the drug or preparation is 1-4 times/day, preferably 1 time/day.
  • the administration time of the drug or preparation is 2 weeks to 5 years, preferably 2 months to 1 year.
  • a method for inhibiting the current of intracellular TREK-1 ion channel comprising the steps of: making the cell expressing TREK-1 ion channel protein and the compound of formula I or its pharmaceutically acceptable acceptable salt exposure, thereby inhibiting the current in the intracellular TREK-1 ion channel.
  • the method is non-therapeutic in vitro.
  • Figure 1 shows the effect experiment of TREK-1 ion channel in Example 2, wherein Figures A, B and C show the IV curve (top), current amplitude (middle) of CLA096 of 5 ⁇ M, 10 ⁇ M and 20 ⁇ M on TREK-1 channel, respectively ) and current inhibition rate (bottom).
  • Figure 2 shows the effect of different doses of CLA096 on the immobility time of forced swimming in the forced swimming experiment of normal mice (Example 3) to evaluate the antidepressant-like effect of CLA096.
  • Figure 3 shows the effect of different doses of CLA096 on the latency of novel environmental feeding inhibition in normal mice's novel environmental feeding inhibition experiment (Example 3) to evaluate the antidepressant-like effect of CLA096. *p ⁇ 0.05, **p ⁇ 0.01, compared with vehicle group.
  • Figure 4 shows the modeling process and the route map of the administration of the rat animal model of treatment-resistant depression (Example 4).
  • Figure 5 shows the efficacy evaluation of adrenocorticotropic hormone-induced rat model of refractory depression (Example 4), wherein Figures AC show the three states of immobility, swimming and climbing in the forced swimming test, respectively , Panel D shows the total locomotion distance of rats in the open field experiment. *p ⁇ 0.05, compared with vehicle group.
  • Figure 6 shows the survival curve of mice in the 14-day subacute experiment of CLA096 (Example 5).
  • Figure 7 shows the body weight change of mice in the 14-day subacute toxicity experiment of CLA096, wherein the left picture is the body weight change of male mice, and the right picture is the body weight change of female mice (Example 5).
  • CLA096 has a significant inhibitory effect on TREK-1 ion channel, and the compound also has excellent in vivo antidepressant ability and low toxicity, so it is very suitable for treatment or prevention.
  • TREK-1 ion channel-related diseases eg, psychiatric disorders including depression
  • the present invention has been completed.
  • the terms “compound of the invention”, “compound of formula I”, “CLA096” and “compound CLA096” are used interchangeably to refer to the compound of formula I (whose name is N-benzyl-2-(N -(4-chlorophenyl)methanesulfonylamino)-N-methylacetamide), the term also includes various crystalline forms, pharmaceutically acceptable salts of compounds of formula I;
  • pharmaceutically acceptable salts refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicines.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the present invention with acids.
  • Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene
  • compositions and methods of administration are provided.
  • the compound of the present invention Since the compound of the present invention has excellent ability to inhibit TREK-1 ion channel and excellent antidepressant effect in vivo, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, and compounds containing the present invention are
  • the pharmaceutical composition of the main active ingredient can be used for the treatment, prevention and/or alleviation of TREK-1 ion channel-related diseases (such as mental disorders) or for the treatment, prevention and/or alleviation of mental disorders such as depression.
  • the compounds of the present invention can be used to treat the following diseases: depression, anxiety, schizophrenia, and/or mental disorders such as bipolar disorder.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention (the compound of formula I) or a pharmacologically acceptable salt thereof in a safe and effective amount.
  • the pharmaceutical composition of the present invention may also include other depression treatment agents or antidepressant drugs (eg, fluoxetine, etc.).
  • the pharmaceutical compositions of the present invention may also include pharmacologically acceptable excipients or carriers.
  • a “safe and effective amount” refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-500 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and can be administered to desired subjects (eg, humans and non-human mammals) by conventional means.
  • desired subjects eg, humans and non-human mammals
  • Representative modes of administration include, but are not limited to, oral administration, injection (eg, intravenous, intramuscular, or subcutaneous), and inhalation (eg, nebulization).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • the dosage form may also contain buffering agents.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner (ie, a sustained release formulation). Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the pharmaceutical combination of the present invention may also be formulated as a powder for nebulization.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the drug is administered to a mammal (eg, a human or non-human mammal), wherein the safe and effective amount is usually at least about 10 micrograms per kilogram of body weight, and in most cases not More than about 50 mg/kg body weight (daily), preferably the dose is about 10 micrograms/kg body weight to about 20 mg/kg body weight, more preferably 1-20 mg/kg body weight, most preferably, 1- 5mg/kg body weight.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • TREK-1 ion channel As used herein, the term “TREK-1 ion channel” and “TREK-1 channel” are used interchangeably.
  • TREK-1 ion channel (TWIK—Related K + Channel 1) is an important member of the potassium channel K2P (Two Pore—Domain Potassium Channels) family.
  • Depression also known as depressive disorder, is a major type of mood disorder characterized by significant and persistent low mood. It can be seen clinically that depression is not commensurate with the situation. Depression can range from depression to grief, low self-esteem and depression, and even pessimism and world-weariness. There may be suicide attempts or behaviors; even stupor occurs; some cases have obvious anxiety and motor agitation; In severe cases, psychotic symptoms such as hallucinations and delusions may occur. Each attack lasts for at least 2 weeks, the elderly or even several years. Most cases tend to have repeated attacks. Most of the attacks can be relieved, and some may have residual symptoms or become chronic.
  • treatment with refractory depression is more difficult and slower.
  • treatment-resistant depression is diagnosed when two or more antidepressant drugs with different mechanisms of action are used in a sufficient amount and a full course of treatment with poor effect (HAMD score reduction rate ⁇ 20%).
  • the current treatment regimen generally requires the administration of multiple combination drugs at high doses, which brings physical and psychological burdens to patients.
  • the compound CLA096 of the present invention has a significant antidepressant effect. Especially for treatment-resistant depression, it also has a significant antidepressant effect.
  • the compound CLA096 of the present invention can produce an antidepressant effect comparable to or even significantly better than the positive drug (fluoxetine) in vivo at a lower dose (such as 5 mg/kg body weight).
  • test or analysis methods used in each example are as follows:
  • Cells were transfected by cationic liposome transfection method, and the target gene TREK-1 plasmid protein was heterologously expressed in CHO-K1 cells according to the operating standard instructions of Lipo3000 transfection reagent. Electrophysiological experiments were performed after ion channel proteins were expressed in cells for 24-48 hours.
  • Electrophysiological experiments were performed in whole-cell patch-clamp recording mode.
  • the transfected cells were placed in a bath containing extracellular fluid, the resistance of the drawn electrode was 3-7M ⁇ , the electrode was filled with intracellular fluid, the polished electrode was used to contact the cell membrane, the positive pressure was removed, and the cell membrane was gently removed.
  • a high-impedance seal is formed by applying negative pressure to the ground, and then the cell membrane is broken by continuing to apply negative pressure, that is, a whole-cell recording mode is formed.
  • the sampling frequency of the electrophysiological amplifier is 10kHz, and the data sampling is controlled by the DigiData 1440A conversion interface.
  • Whole cell recording experiment data collection and analysis software is Clamfit10.7, data analysis and graphing software is
  • Origin8.1 the software for statistical analysis of data is SPSS.
  • the open field test also known as the open-box test, is a method to evaluate the autonomous behavior, exploratory behavior and anxiety-like behavior of experimental animals in a novel environment.
  • the frequency and duration of the normal activities of the experimental animals in the open box, the fear of the open environment and the exploration of the new environment, etc., are used to reflect the autonomous behavior and exploratory behavior of the experimental animals in the unfamiliar environment. Depression and anxiety-like behaviors can be assessed by analyzing the results of animal open field experiments.
  • mice 2 hours before the experiment, the experimental animals were placed in the behavior room to adapt. During the experiment, the animals were placed in the center of the bottom surface of a black plastic box (size 100*100*45cm), and video recording was performed at the same time. The experiment time was 10 minutes and ensured to be carried out in a quiet environment. Wipe the bottom and inner wall of the open box after each experiment to prevent the interference of the remaining animal information from the previous experiment to the next experiment.
  • Use animal spontaneous activity analysis software to analyze the video, and obtain information such as the central area activity time (anxiety-like behavior), total activity distance (exercise ability), and wall climbing times (novel environment exploration behavior) of animals, which can be used for animal depression. or anxiety-like behavior and its degree.
  • the forced swimming test system is mainly used for antidepressant research. Placing experimental animals in a confined environment (such as water) in which animals struggle exclusively to escape but cannot escape, thus providing an unavoidable oppressive environment, and after a period of experimentation, animals exhibit typical
  • the "immobility state” reflects a so-called “behavioral despair state", which records a series of parameters in the process of animals in this environment producing a hopeless immobility state.
  • mice were individually placed in a cylindrical glass jar with a height of 30 cm and a diameter of 20 cm, and the water depth in the tank was 15 cm (the water depth of the rat was 20 cm), so that the mice could not escape from the glass jar, and their feet and tails Without touching the bottom of the tank, the water temperature is 23°C-25°C.
  • the video was taken 6 minutes after the mice entered the water. Since most mice were very active in the first two minutes, the immobility time after 4 minutes was calculated (the standard for determining immobility: the mice stopped struggling in the water, did not move and did not move in order to maintain balance or show signs of movement). small limb movements in a floating state).
  • the mice in each group were operated in parallel.
  • Novelty-suppressed feeding is a conflict between feeding and fear of the new environment in a novel environment under starvation after fasting animals.
  • Long-term administration of antidepressants can improve the animals' ability to respond to the conflict. Decreased, manifested as a shortened latency to start feeding, this model is currently widely used in the evaluation of antidepressant and anxiolytic efficacy.
  • the experimental equipment is a 35cm*35cm*30cm (length*width*height) open box, the open box is covered with bottom material, a white filter paper with a diameter of 5cm is placed in the open box, and 2 grains of food are placed in the middle of the filter paper. Animals were fasted for 12 h before administration.
  • the novel environmental feeding inhibition experiment was performed 1h and 24h after administration, respectively.
  • the experimental operation was as follows. The animal was placed from the edge of the experimental open box, and the animal touched the food with its mouth within 10 minutes, which was regarded as the animal successfully feeding, and the animal was immediately taken out, and the time of its successful feeding (ie Novelty latency) was calculated. After that, the animals were put into the normal feeding cages, and the time from the animals to feeding was also calculated (ie Habituation latency).
  • Step 2 Sodium bicarbonate (156.10g, 1.86mol) was dispersed in dichloromethane (0.5L), and a solution of bromoacetyl bromide (274.83g, 1.36mol) in dichloromethane (0.5L) was added dropwise through a dropping funnel, After adding nitrogen and replacing three times, the ice-water bath was cooled to 0 to 5 degrees, and a solution of N-methylbenzylamine (150.00g, 1.24mol) in dichloromethane (0.5L) was slowly added dropwise through a dropping funnel.
  • Step 3 Intermediate 1 (232.0g, 1.13mol), Intermediate 2 (309.9g, 1.28mol) and potassium carbonate (235.0g, 1.70mol) were dispersed in acetonitrile (2.5L), heated under reflux and stirred for 2 hours, HPLC It shows that the reaction of the starting materials is complete.
  • CLA096 A total of three doses were set in this experiment, which were first dissolved in DMSO, and then diluted with three-distilled water to high, medium and low doses, respectively: 5 ⁇ M, 10 ⁇ M and 20 ⁇ M.
  • the method of patch clamp was used to record the current of TREK-1 ion channel in whole cell.
  • Select Protocol A0 to record the currents of cells at -80mV, -60mV, -40mV, -20mV, 0mV, 20mV, 40mV, 60mV, and 80mV, repeat Protocol A0, and administer 5 ⁇ M, 10 ⁇ M, and 20 ⁇ M of CLA096 at different concentrations, respectively. After dosing, it was tested for its ability to elute.
  • CLA096 can inhibit the open current of TREK-1 channel, and the inhibition rates of 5 ⁇ M, 10 ⁇ M and 20 ⁇ M CLA096 are 0.75 ⁇ 0.02, 0.55 ⁇ 0.05 and 0.59 ⁇ 0.01, respectively, indicating that CLA096 has a positive effect on TREK-1 channel. higher inhibitory activity.
  • the present invention selects C57 mice, and conducts two kinds of antidepressant behavioral drug effect experiments, and uses different doses of CLA096 by intraperitoneal injection.
  • the effect of the control drug fluoxetine can therefore be used as an application for preparing a drug for treating depression.
  • CLA096 There are three doses in this experiment. The high, medium and low doses are respectively: 5mg/kg, 20mg/kg and 40mg/kg.
  • the compound is dissolved in 0.5% Tween-40 and needs ultrasonic solubilization. It is prepared and used now.
  • Fluoxetine (FLX): The dose of FLX is 10 mg/kg; it is dissolved in double distilled water and is ready for use.
  • FIG. 1 Mice forced swimming experiment Figure 2 shows the immobility time (s) of the mice in the forced swimming test.
  • the results show that fluoxetine significantly reduces the immobility time of animals in water, and CLA096 can significantly reduce the immobility time at each dose. immobility time of animals, and the effect of CLA096 was significantly better than that of fluoxetine.
  • the immobility time of forced swimming reflects the desperate behavior of animals in an inescapable environment, and is also a common depressive symptom. It can be seen that CLA096 has a significant antidepressant effect (data analysis using One-way ANOVA with LSD post-hoc tests: *p ⁇ 0.05 , **p ⁇ 0.01, ***p ⁇ 0.001, compared with the vehicle control group).
  • Figure 3 shows the results of a compound determination of latency (time, s) to go to food in fasted mice.
  • the value of the latency period reflects the motivation of mice in a physiological sense, which is one of the clinical symptoms of depression and can also be used to describe anxiety symptoms. In general, the longer the incubation period, the more severe the depressive symptoms.
  • Different doses of CLA096 can significantly reduce the latency value, and it is significantly better than fluoxetine (data analysis using One-way ANOVA with LSD post-hoc tests: *p ⁇ 0.05, **p ⁇ 0.01, compared with the vehicle control group ).
  • CLA096 has significant antidepressant effect, and at three doses, high, medium and low, the antidepressant effect of CLA096 is better than that of the positive control drug fluoxetine.
  • CLA096 has the ability to have significant antidepressant-like behavior at low doses.
  • SD rats were injected intraperitoneally with adrenocorticotropic hormone (ACTH) for 3 weeks to induce an animal model of treatment-resistant depression.
  • ACTH adrenocorticotropic hormone
  • This model can block the effects of tricyclic antidepressants and some SSRIs, but not ketamine. (ketamine) and electroshock therapy (ETC). Since ketamine and ETC have special effects on treatment-resistant depression, this animal model can preliminarily evaluate whether the drugs have curative effects on treatment-resistant depression.
  • test drug was administered for 30 minutes. After a single dose of the test drug was administered for 30 minutes, an open field experiment was performed.
  • Tested drug configuration CLA096: There are three doses in this experiment: 5mg/kg, 50mg/kg and 100mg/kg.
  • Solvent control group 163.5 ⁇ l DMSO, then add 327 ⁇ l Tween-80, and finally add three distilled water to dissolve in 3ml.
  • Animal grouping 20 male mice and 20 female mice were randomly divided into 4 groups, as shown in the following table:
  • CLA096 has significant and excellent antidepressant effect, and has good safety.

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Abstract

本发明提供了一种预防和治疗精神障碍性疾病的化合物及其应用。具体地，本发明提供了式I化合物或其药学上可接受的盐的用途，用于(i)制备预防和/或治疗TREK-1离子通道相关疾病的药物组合物或制剂，(ii)制备预防和/或治疗精神障碍类疾病的药物组合物或制剂和/或(iii)制备TREK-1离子通道抑制剂。

Description

一种预防和治疗精神障碍性疾病的化合物及其应用 技术领域
本发明涉及药物化学领域，更具体地涉及一种预防和治疗精神障碍性疾病的化合物及其应用。
背景技术
抑郁症是一种常见的心境障碍，严重者可出现自杀念头和行为，人群中有16％的人会在其一生的某个时期受其影响。抑郁障碍是具有高患病率、高复发率、高致残率以及高自杀率等特点的一类严重的精神障碍性疾病。抑郁症在严重影响患者身心健康的同时也带来不小的经济负担。从临床诊断学、病理机制以及治疗结局上综合分析，抑郁障碍都是一类极为复杂的精神疾病。
重度抑郁症(MDD)是严重的精神障碍疾病，一般具有较低康复率和较高的复发率，慢性病率约为20％。全球每年因重度抑郁症导致的成本约为830亿美元，其中，主要包括社会心理功能(尤其是劳动力绩效)下降所引起的间接成本等。
难治性抑郁(TRD)源于对MDD的治疗目标。广义上讲，治疗MDD的首要目标是使受影响的个体不再具有临床上显著的症状和/或功能障碍(例如，在工作，个人和家庭生活中)而达到完全康复的状态。在临床上，通过两个或更多个适当的抗抑郁药治疗未能达到缓解的都属于TRD。
目前抗抑郁药的作用靶点以单胺类受体和转运体为主，但是这些临床一线药物存在起效慢、个体差异大以及30％的患者无效等缺陷。
综上所述，本领域迫切需要开发新型抗抑郁症药物。
发明内容
本发明的目的就是提供一种新型治疗或预防精神障碍类疾病(如抑郁症)的药物。
在本发明的第一方面，提供了一种式I化合物或其药学上可接受的盐的用途，其特征在于，用于(i)制备预防和/或治疗TREK-1离子通道相关疾病的药物组合物或制剂，(ii)制备预防和/或治疗精神障碍类疾病的药物组合物或制剂和/或(iii)制备TREK-1离子通道抑制剂；
Figure PCTCN2021109365-appb-000001
在另一优选例中，所述的式I化合物是化合物CLA096，即N-苄基-2-(N-(4-氯苯基)甲磺酰氨基)-N-甲基乙酰胺。
在另一优选例中，所述的TREK-1离子通道相关疾病是指能够通过抑制TREK-1离子通道被治疗或预防或改善的疾病。
在另一优选例中，所述的与TREK-1离子通道相关疾病包括精神障碍类疾病。
在另一优选例中，所述的精神障碍类疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的TREK-1离子通道相关疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的抑郁症包括：重度抑郁症和/或难治性抑郁症。
在另一优选例中，所述的预防和/或治疗TREK-1离子通道相关疾病包括：抗抑郁、抗焦虑、抗精神分裂、抗双相情感障碍、或其组合。
在另一优选例中，所述的预防和/或治疗精神障碍类疾病包括：抗抑郁、抗焦虑、抗精神分裂、抗双相情感障碍、或其组合。
在另一优选例中，所述的药物组合物还包含一种或多种选自下组的另外的活性成分：
(i)TREK-1离子通道抑制剂；
(ii)用于治疗或预防精神障碍类疾病的药物。
在另一优选例中，所述另外的活性成分不是式I化合物和其药学上可接受的盐。
在另一优选例中，所述用于治疗或预防精神障碍类疾病的药物包括治疗抑郁的活性成分或者抗抑郁药物。
在另一优选例中，所述的药物组合物还含有其他治疗抑郁的活性成分。
在另一优选例中，所述式I化合物的施用剂量为0.1-50mg/kg体重，较佳地为1-5mg/kg体重。
在另一优选例中，所述式I化合物的施用剂量≤50mg/kg体重时，无不良反应。
在另一优选例中，所述的不良反应包括：体重明显变化和死亡。
在另一优选例中，所述的药物组合物中含有0.001-99wt％的式I化合物或其药学上可接受的盐，按所述药物组合物的总重量计。
在另一优选例中，所述药物组合物中含有0.1-90wt％，较佳地1-80wt％的式I化合物或其药学上可接受的盐，按组合物的总重量计。
在另一优选例中，所述的药物组合物的剂型包括口服剂型、注射剂和/或吸入剂型。
在另一优选例中，所述口服剂型包括：片剂、胶囊剂、膜剂、和/或颗粒剂。
在另一优选例中，所述口服剂型为缓释剂型或非缓释型剂型。
在本发明的第二方面，提供了一种药物组合物，所述药物组合物包含式I化合物或其药学上可接受的盐。
在另一优选例中，所述的药物组合物还包含一种或多种选自下组的另外的活性成分：
(i)TREK-1离子通道抑制剂；
(ii)用于治疗或预防精神障碍类疾病的药物。
在另一优选例中，所述另外的活性成分不是式I化合物和其药学上可接受的盐。
在另一优选例中，所述用于治疗或预防精神障碍类疾病的药物包括治疗抑郁症的活性成分或者抗抑郁药物。
在另一优选例中，所述的药物组合物还包含其他治疗抑郁症的活性成分或者抗抑郁药物。
在另一优选例中，所述的药物组合物中还包含药学上可接受的载体。
在另一优选例中，所述的式I化合物或其药学上可接受的盐的总含量为所述药物组合物的0.001-99wt％，较佳地0.1-90wt％，更佳地1-80wt％。
在另一优选例中，所述的药物组合物用于预防和/或治疗TREK-1离子通道相关疾病。
在另一优选例中，所述的药物组合物用于预防和/或治疗精神障碍类疾病。
在另一优选例中，所述的与TREK-1离子通道相关疾病包括精神障碍类疾病。
在另一优选例中，所述的精神障碍类疾病包括：抑郁症(包括重度抑郁症和/或难治性抑郁症)、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的药物组合物用于预防和/或治疗重度抑郁症。
在另一优选例中，所述的药物组合物用于预防和/或治疗难治性抑郁症。
在本发明的第三方面，提供了一种TREK-1离子通道抑制剂，所述的抑制剂包 括如式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2021109365-appb-000002
在本发明的第四方面，提供了一种预防和/或治疗TREK-1离子通道相关疾病的方法，包括步骤：向需要的对象施用式I化合物或其药学上可接受的盐；其中，所述式I化合物如第一方面中定义。
在另一优选例中，所述的TREK-1离子通道相关疾病为精神障碍类疾病。
在另一优选例中，所述的精神障碍类疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的TREK-1离子通道相关疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的对象包括：人，或非人哺乳动物。
在另一优选例中，所述的非人哺乳动物包括：灵长目动物，或啮齿类动物(如小鼠、大鼠等)。
在另一优选例中，所述施用的施用剂量为1～20mg/kg体重，较佳地为5mg/kg体重。
在另一优选例中，所述施用的频率为1-4次/天，较佳地为1次/天。
在另一优选例中，所述施用的施用每日总剂量为1～20mg/kg体重，较佳地为5mg/kg体重。
在另一优选例中，所述施用的时间为2周-5年，较佳地为2月～1年。
在本发明的第五方面，提供了一种预防和/或治疗精神障碍类疾病的方法，包括步骤：向需要的对象施用式I化合物或其药学上可接受的盐；其中，所述式I化合物如第一方面中定义。
在另一优选例中，所述的精神障碍类疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
在另一优选例中，所述的精神障碍类疾病为抑郁症。
在另一优选例中，所述的对象包括：人，或非人哺乳动物。
在另一优选例中，所述的非人哺乳动物包括：灵长目动物，或啮齿类动物(如小鼠、大鼠等)。
在另一优选例中，所述施用的施用剂量为1～20mg/kg体重，较佳地为5mg/kg体重。
在另一优选例中，所述施用的频率为1-4次/天，较佳地1次/天。
在另一优选例中，所述施用的施用每日总剂量为1～20mg/kg体重，较佳地为5mg/kg体重。
在另一优选例中，所述施用的时间为2周-5年，较佳地为2月～1年。
在本发明的第六方面，提供了一种药盒，所述的药盒包括：
(i)含式I化合物或其药学上可接受的盐作为活性成分的药物或制剂；和
(ii)说明书。
在另一优选例中，所述的说明书中记载有该药盒的适应症包括：精神障碍类疾病；较佳地，适应症包括：抑郁症(重度抑郁症和/或难治性抑郁症)、焦虑症、精神分裂症、和/或双向情感障碍。
在另一优选例中，所述的说明书中记载有所述药物或制剂的施用的剂量为1～20mg/kg体重，较佳地为5mg/kg体重，以活性成分计。
在另一优选例中，所述药物或制剂的施用频率为1-4次/天，较佳地1次/天。
在另一优选例中，所述药物或制剂的施用时间为2周-5年，较佳地为2月～1年。
在本发明的第七方面，提供了一种抑制细胞内TREK-1离子通道的电流的方法，所述的方法包括步骤：使表达TREK-1离子通道蛋白的细胞与式I化合物或其药学上可接受的盐接触，从而抑制细胞内TREK-1离子通道的电流。
在另一优选例中，所述的方法是体外非治疗性的。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了实施例2的TREK-1离子通道作用效果实验，其中图A、B和C分别显示了5μM、10μM和20μM的CLA096对TREK-1通道的I-V曲线(上)、电流幅度(中)和电流抑制率(下)的影响。
图2显示了正常小鼠的强迫游泳实验(实施例3)中不同剂量CLA096对强迫游泳的不动时间的的影响，以评价CLA096的抗抑郁样作用。*p<0.05,**p<0.01,***p<0.001,与溶媒组比较。
图3显示了正常小鼠的新异环境摄食抑制实验(实施例3)中不同剂量CLA096新异环境摄食抑制的潜伏期的影响，评价CLA096的抗抑郁样作用。*p<0.05,**p<0.01，与溶媒组比较。
图4显示了大鼠难治性抑郁症动物模型的造模过程及给药的路线图(实施例4)。
图5显示了促肾上腺皮质激素致大鼠难治性抑郁症模型的药效评价(实施例4)，其中图A-C分别显示了强迫游泳实验中大鼠的不动、游泳和攀爬三种状态，图D显示了旷场实验中大鼠的总运动路程。*p<0.05,与溶媒组比较。
图6显示了CLA096的14天亚急毒实验中小鼠的生存曲线(实施例5)。
图7显示了CLA096的14天亚急毒实验中小鼠的体重变化，其中左图为雄性小鼠的体重变化，右图为雌性小鼠的体重变化(实施例5)。
具体实施方式
本发明人经广泛而深入地研究，意外地发现CLA096对TREK-1离子通道具有显著的抑制作用，并且该化合物同时还具有优异的体内抗抑郁能力和低毒性，因此十分适合用于治疗或预防TREK-1离子通道相关疾病(例如，包括如抑郁症在内的精神障碍类疾病)或者用于治疗或预防精神障碍类疾病。在此基础上，完成了本发明。
尤其是，本文中对CLA096进行了多种抗抑郁症的行为学药效实验，实验通过使用不同剂量CLA096的经腹腔注射的给药方式，结果发现该化合物CLA096具有显著的抗抑郁效果，其作用优于阳性对照氟西汀的作用，因此十分适于应用于制备治疗抑郁症药物中。
术语
在本文中，除非特别说明，各缩写具有本领域技术人员理解的常规含义，例如，“Ms”是指甲磺酰基。
活性成分
如本文所用，术语“本发明化合物”、“式I化合物”、“CLA096”和“化合物CLA096”可以互换使用是指式I所示的化合物(其名称为N-苄基-2-(N-(4-氯苯基) 甲磺酰氨基)-N-甲基乙酰胺)，该术语还包括式I化合物的各种晶型形式、药学上可接受的盐；
Figure PCTCN2021109365-appb-000003
其中，术语“药学上可接受的盐”是指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
药物组合物和施用方法
由于本发明化合物具有优异的抑制TREK-1离子通道的能力以及优异的体内抗抑郁作用，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防和/或缓解与TREK-1离子通道相关疾病(如精神障碍类疾病)或者用于治疗、预防和/或缓解精神障碍类疾病如抑郁症。根据现有技术，本发明化合物可用于治疗以下疾病：抑郁症、焦虑症、精神分裂症、和/或双相情感障碍等精神障碍类疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物(式I化合物)或其药理上可接受的盐。本发明的药物组合物还可包括其他抑郁症治疗剂或抗抑郁药物(如氟西汀等)。本发明的药物组合物还可包括药理上可以接受的赋形剂或载体。
“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元 醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021109365-appb-000004
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，可以通过常规方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于)：口服、注射(如静脉内、肌肉内或皮下)和吸入(如雾化吸入)等给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放(即缓释制剂)。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合 物。
本发明的药物组合也可以被制成粉剂用于雾化吸入。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用本发明药物组合物时，是将安全有效量的药物施用于哺乳动物(如人或非人哺乳动物)，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约50毫克/千克体重(每日)，较佳地该剂量是约10微克/千克体重-约20毫克/千克体重，更佳地，为1～20mg/kg体重，最佳地，1-5mg/kg体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
TREK-1离子通道
如本文所用，属于“TREK-1离子通道”和“TREK-1通道”可以互换使用。TREK-1离子通道(TWIK—Related K +Channel 1)是指钾通道K2P通道(Two Pore—Domain Potassium Channels)家族重要的一员。
抑郁症
抑郁症又称抑郁障碍，以显著而持久的心境低落为主要临床特征，是心境障碍的主要类型。临床可见心境低落与其处境不相称，情绪的消沉可以从闷闷不乐到悲痛欲绝，自卑抑郁，甚至悲观厌世，可有自杀企图或行为；甚至发生木僵；部分病例有明显的焦虑和运动性激越；严重者可出现幻觉、妄想等精神病性症状。每次发作持续至少2周以上、长者甚或数年，多数病例有反复发作的倾向，每次发作大多数可以缓解，部分可有残留症状或转为慢性。
抑郁症中又以难治性抑郁的治疗更难，更缓慢。在临床上，通过应用作用机制不同的抗抑郁药物两种或两种以上足量足疗程治疗后效果欠佳(HAMD减分率<20％)，就被诊断为难治性抑郁症。现行的治疗方案一般需要尝试多种组合药物的高剂量下给药，给患者带来身体和心理的负担。
本发明的主要优点包括：
(a)本发明的化合物CLA096具有显著的抗抑郁作用。尤其是对于难治性抑郁症也具有显著的抗抑郁效果。
(b)本发明的化合物CLA096具有优异的安全性。
(c)本发明的化合物CLA096在更低剂量(如5mg/kg体重)下就能在体内产生 与阳性药物相当甚至显著优于阳性药物(氟西汀)的抗抑郁效果。
(d)本发明的化合物CLA096在大鼠和小鼠上均显示显著的抗抑郁作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非特别说明，各实施例中所用的测试或分析方法如下：
TREK-1点生理实验实验方法
细胞转染
细胞转染采用阳离子脂质体转染方法，按照Lipo3000转染试剂的操作标准说明，将目的基因TREK-1质粒蛋白异源表达于CHO-K1细胞中。离子通道蛋白在细胞内表达24-48h后进行电生理实验。
电生理实验及数据分析
电生理实验采用全细胞膜片钳记录模式。将转染后的细胞放置于含有细胞外液的浴池中，拉制的电极电阻为3-7MΩ，在电极中灌入细胞内液，用进行抛光后的电极接触细胞膜，撤去正压并轻轻地给予负压吸引形成高阻抗封接，然后采用继续施加负压的方法打破细胞膜，即形成了全细胞记录模式。电生理放大器的采样频率为10kHz，数据的采样采用DigiData 1440A转换接口控制。全细胞记录实验数据采集并分析使用软件为Clamfit10.7，数据分析与作图使用软件为
Origin8.1，数据统计分析使用软件为SPSS。
动物行为学方法：
旷场试验(OPT)
旷场实验(open field test)又称敞箱实验，是评价实验动物在新异环境中自主行为、探究行为与焦虑样行为的一种方法。以实验动物在敞箱之中的正常活动、惧怕空旷环境和探索新环境等行为的发生频率和持续时间等，来反映实验动物在陌生环境中的自主行为与探究行为。分析动物旷场实验结果可对动物进行抑郁及焦虑样行为评估。
实验操作：实验前2小时将实验动物置于行为室适应。实验时将动物放于黑色塑料箱(大小为100*100*45cm)底面中心，同时进行视频拍摄，实验时间10分 钟并保证在安静的环境下进行。每次实验后擦拭敞箱底部及内壁，防止上次动物余留信息对下次实验的干扰。利用动物自发活动分析软件对视频进行分析，得出动物的中央区域活动时间(焦虑样行为)、活动总路程(运动能力)、爬壁次数(新异环境探索行为)等信息，可以对动物抑郁或焦虑样行为及程度进行评判。
强迫游泳试验(FST)
强迫游泳实验系统主要用于抗抑郁的研究。将实验动物置于一个局限的环境中(如水中)，动物在该环境中拼命挣扎试图逃跑又无法逃脱，从而提供了一个无可回避的压迫环境，一段时间的实验后，动物即表现出典型的“不动状态”，反映了一种被称之为“行为绝望状态”，记录处于该环境的动物产生绝望的不动状态过程中的一系列参数。
实验操作：将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米(大鼠水深20厘米)，使老鼠既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后6分钟视频，由于大多数小鼠在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
新异环境摄食实验
新异环境抑制摄食实验(novelty-suppressed feeding,NSF)是动物禁食后在饥饿状态下新奇的环境中产生摄食和对新环境恐惧的矛盾冲突,长期给予抗抑郁药物可使动物的冲突反应能力降低，表现为开始摄食的潜伏期缩短，该模型目前被广泛应用于抗抑郁和抗焦虑的药效评价。
实验设备为35cm*35cm*30cm(长*宽*高)的敞箱，敞箱中铺满底料，敞箱中放入直径为5cm的白色滤纸，滤纸中间放入2粒食物。动物给药前动物禁食12h。
行为测试前2h，将动物移入功能房适应环境2h。按照上述给药方案，给予药物干预。分别在给药后1h和24h做新异环境摄食抑制实验，实验操作如下。将动物从实验敞箱的边缘放入，动物在10min之内嘴碰触到食物，视为动物成功取食，即刻将动物取出，并计算其成功取食的时间(即Novelty latency)。之后再将动物放入正常饲养笼子，也计算动物从放入到取食的时间(即Habituation latency)。如果动物在10min之内未成功获取食物，强制取出动物，同样放入正常饲养笼子，同时计算其habituation latency。实验全过程有摄像头录制，并在线下处理及分析数据。
实施例1 CLA096的制备
Figure PCTCN2021109365-appb-000005
合成路线：
Figure PCTCN2021109365-appb-000006
步骤一：对氯苯胺(150.00g,1.18mol)溶于二氯甲烷(1.25L)中，室温下一次性加入吡啶(102.83g,1.30mol)，反应体系温度未发生变化。氮气置换三次，冰水浴冷却至0～5度，缓慢滴入甲基磺酰氯(148.67g,1.30mol)，滴毕，升至室温搅拌过夜，TLC(PE:EA＝3:1)显示原料对氯苯胺反应完。将反应液倒入水(2.0L)中淬灭，有固体析出，过滤，滤饼水洗，干燥得到浅粉色固体中间体1(236.80g,收率98％)。HPLC：99.73％purity,220nm； 1H NMR：(400MHz,DMSO-d6)δ9.87(s,1H),7.43-7.36(m,2H),7.24-7.17(m,2H),2.99(s,3H).
步骤二：碳酸氢钠(156.10g,1.86mol)分散至二氯甲烷(0.5L)中，通过滴液漏斗滴加溴乙酰溴(274.83g,1.36mol)的二氯甲烷(0.5L)溶液，加完氮气置换三次，冰水浴冷却至0～5度，通过滴液漏斗缓慢滴加N-甲基苄胺(150.00g,1.24mol)的二氯甲烷(0.5L)溶液，滴毕，升至室温搅拌1小时，HPLC显示原料N-甲基苄胺还有部分剩余，冰水浴冷却至0～5度，补加溴乙酰溴(75.00g,0.37mol)，室温搅拌过夜，HPLC显示N-甲基苄胺仍有少量剩余。反应液倒入冰水(1.5L)中淬灭，分液，二氯甲烷萃取，合并有机相，浓缩部分有机相，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析(PE:EA＝10:1～4:1)纯化，得到无色油状产品中间体2(200g,收率67％)。HPLC：(98.75％purity,220nm)
步骤三：中间体1(232.0g,1.13mol)，中间体2(309.9g,1.28mol)和碳酸钾(235.0g,1.70mol)分散至乙腈(2.5L)中，加热回流搅拌2小时，HPLC显示原料反应完。反应液降至室温，加水(1.5L)淬灭，分液，乙酸乙酯萃取，合并有机相，浓缩部分有机相，水洗，无水硫酸钠干燥，过滤，浓缩，得到淡黄色油状物粗品， 经硅胶柱层析(石油醚:乙酸乙酯＝10:1～4:1)纯化，得到类白色固体CLA096(245.6g,收率59％)。LCMS：m/z＝367.1[M+H] +，HPLC：(99.33％purity,220nm)， 1H NMR(400MHz,DMSO-d 6)δ7.53-7.44(m,4H),7.38-7.23(m,3H),7.19-7.10(m,2H),4.70-4.67(m,2H),4.56-4.49(m,2H),3.14(s,3H),2.91-2.81(m,3H).
实施例2 CLA096对TREK-1通道的作用
具体实施方式：
受试药物：CLA096
受试药物配置
CLA096：本实验共设三个剂量，先用DMSO溶解后，再用三蒸水稀释至高中低剂量，分别为：5μM、10μM和20μM。
实验采用胞膜片钳的方法，全细胞记录TREK-1离子通道的电流。选择Protocol A0记录-80mV、-60mV、-40mV、-20mV、0mV、20mV、40mV、60mV和80mV下细胞的电流，重复Protocol A0，分别灌流给药5μM，10μM和20μM，等不同浓度的CLA096。给药结束后，测试其是否能够洗脱。
结果如图1所示，CLA096能够抑制TREK-1通道的开放电流，其中5μM，10μM和20μM CLA096的抑制率分别为0.75±0.02，0.55±0.05和0.59±0.01，表明CLA096对TREK-1通道有较高的抑制活性。
实施例3化合物CLA096在C57小鼠的抗抑郁症作用
本发明选用C57小鼠，进行了两种抗抑郁症的行为学药效实验，经腹腔注射给药方式，使用不同剂量CLA096，结果发现该化合物CLA096具有显著的抗抑郁效果，其作用优于阳性对照药氟西汀的作用，因此可作为制备治疗抑郁症药物的应用。
实验过程及具体结果如下：
受试药物：
CLA096,氟西汀(FLX，Fluoxetine)
受试药物配置
CLA096：本实验共设三个剂量，高中低剂量分别为：5mg/kg、20mg/kg和40mg/kg,化合物溶于0.5％吐温-40，需超声助溶，现配现用。
氟西汀(FLX)：FLX剂量为10mg/kg；溶于双蒸水，现配现用。
溶剂对照组(Veh)：0.5％吐温-40。
数据分析：
所有数据分析采用spss 22(for mac)数据处理软件完成。使用单因素方差分析，采用LSD法多重比较校验结果。
动物分组
60只8周龄C57雄性小鼠，随机分成5组，各组如下表所示：
Figure PCTCN2021109365-appb-000007
实验结果
1.小鼠强迫游泳实验图2显示了小鼠在强迫游泳测试中的不动时间(s)，结果显示氟西汀显著降低动物在水中的不动时间，CLA096在各个剂量下均能显著降低动物的不动时间，并且CLA096的效果显著优于氟西汀。强迫游泳的不动时间反映动物在不可逃避环境中的绝望行为，也是常见的抑郁症状，可见CLA096具有显著的抗抑郁效果(数据分析采用One-way ANOVA with LSD post-hoc tests:*p<0.05,**p<0.01，***p<0.001，与溶媒对照组比较)。
2.新异环境摄食抑制实验
图3显示了化合物对经过禁食的小鼠去取食的潜伏期(时间，s)的测定结果。其中潜伏期的值在生理意义上体现了小鼠的动机(motivation)，是抑郁的临床症状之一，也可用来描述焦虑症状。一般情况下，潜伏期越长代表抑郁症状越严重。不同剂量的CLA096都能明显的降低潜伏期值，且明显优于氟西汀(数据分析采用One-way ANOVA with LSD post-hoc tests:*p<0.05,**p<0.01，与溶媒对照组比较)。
综合上述两种抗抑郁的行为学药效实验结果，表明CLA096具有显著的抗抑郁效果，且在高中低三个剂量下，CLA096抗抑郁作用均优于阳性对照药氟西汀，可见本发明的CLA096能够在低剂量下具有显著抗抑郁样行为的的能力。
实施例4 CLA 096在难治性抑郁大鼠模型的抗抑郁药效研究
造模方法：
SD大鼠连续3周腹腔注射促肾上腺皮质激素(ACTH)，诱导难治性抑郁症动物模 型，该模型可以阻断三环类抗抑郁药及部分SSRIs抗抑郁药的作用，但是不能阻断氯胺酮(ketamine)和电击疗法(ETC)的疗效。由于氯胺酮和ETC对难治性抑郁症有特殊疗效，所以该动物模型可以初步评价药物是否具有难治性抑郁症的疗效。
实验流程大致如图4所示，具体步骤如下：
1.模型组(ACTG)中SD大鼠连续注射ACTH 3周(1次/天)，并在ACTH末次给药后的24h腹腔注射受试药物。对照组(CON)大鼠连续腹腔注射0.9％生理盐水(1次/天)，同样在末次给予生理盐水后的24h腹腔注射受试药物。
2.单次剂量给予受试药物30min后，进行旷场实验。
3.旷场实验结束后，继续注射ACTH，过24h后，再腹腔注射以上受试药物，并在给药后的30min检测强迫游泳。
实验分组：
各分组如下表所示：
Figure PCTCN2021109365-appb-000008
1.大鼠强迫游泳结果
大鼠强迫游泳结果显示(图5.A-C)，CLA096以及阳性药丙咪嗪、氯胺酮显著降低控制(CON)组大鼠强迫游泳的不动时间(图5A)，并且CLA096显著提高大鼠的游泳时间(图5B)，表明CLA096急性给药抗抑郁药效显著。大鼠经ACTH造模(ACTH组大鼠)后，三环类抗抑郁药丙咪嗪的抗抑郁作用被阻断，而氯胺酮和CLA096的抗抑郁药效仍显著，表明CLA096对难治性抑郁症有疗效(数据分析采用One-way ANOVA with LSD post-hoc tests:*p<0.05，与溶媒对照组比较)。
2.大鼠旷场实验结果
大鼠旷场结果(图5D)显示，CLA096和氯胺酮虽然对正常动物和ACTH模型动物的总运动路程有增加的趋势，但无显著差异，表明CLA096对大鼠的运动能力无显著性影响。
实施例5 CLA096的14天亚急毒实验
具体实施方式：
受试药物：CLA096
受试药物配置：CLA096：本实验共设三个剂量，分别为：5mg/kg、50mg/kg和100mg/kg。
5mg/kg:取母液8.2μl,再加155.3μl DMSO,再加入吐温(Tween)-80为327μl,充分混匀后，最后加三蒸水定溶于3ml，三蒸水缓慢滴加，防止药品析出。
50mg/kg:取母液81.8μl,再加81.7μl DMSO,再加入吐温-80为327μl,充分混匀后，最后加三蒸水定溶于3ml，三蒸水缓慢滴加，防止药品析出。
100mg/kg:取母液163.5μl,再加入吐温-80为327μl，最后加三蒸水定溶于3ml，三蒸水缓慢滴加，防止药品析出。
溶剂对照组：163.5μl DMSO,再加入327μl Tween-80,最后加三蒸水定溶于3ml。
动物分组：20只雄性老鼠和20只雌性老鼠分别随机分成4组，具体分组如下表所示：
Figure PCTCN2021109365-appb-000009
从如图6所示的小鼠生存曲线图中可以看出，CLA096的低、中和高剂量组对小鼠均不致死。而且对于不同性别的老鼠组均未出现体重明显变化的情况(见图7)。
综合上述行为学药效实验结果，表明CLA096具有显著且优异的抗抑郁效果，且具有良好的安全性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 一种式I化合物或其药学上可接受的盐的用途，其特征在于，用于(i)制备预防和/或治疗TREK-1离子通道相关疾病的药物组合物或制剂，(ii)制备预防和/或治疗精神障碍类疾病的药物组合物或制剂，和/或(iii)制备TREK-1离子通道抑制剂；
    Figure PCTCN2021109365-appb-100001
  2. 如权利要求1所述的用途，其特征在于，所述的TREK-1离子通道相关疾病包括精神障碍类疾病。
  3. 如权利要求1或2所述的用途，其特征在于，所述的精神障碍类疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
  4. 如权利要求3所述的用途，其特征在于，所述的抑郁症包括：重度抑郁症和/或难治性抑郁症。
  5. 如权利要求1所述的用途，其特征在于，所述式I化合物的施用剂量为0.1-50mg/kg体重，较佳地为1-5mg/kg体重。
  6. 如权利要求1所述的用途，其特征在于，所述的药物组合物中含有0.001-99wt％的式I化合物或其药学上可接受的盐，按所述药物组合物的总重量计。
  7. 如权利要求1所述的用途，其特征在于，所述的药物组合物的剂型包括口服剂型、注射剂和/或吸入剂型。
  8. 一种药物组合物，其特征在于，所述药物组合物包含式I化合物或其药学上可接受的盐。
  9. 如权利要求8所述的药物组合物，其特征在于，所述的药物组合物还包含一种或多种选自下组的另外的活性成分：
    (i)TREK-1离子通道抑制剂；
    (ii)用于治疗或预防精神障碍类疾病的药物。
  10. 如权利要求8所述的药物组合物，其特征在于，所述的药物组合物中还包含药学上可接受的载体。
  11. 一种预防和/或治疗TREK-1离子通道相关疾病的方法，包括步骤：向需要的对象施用式I化合物或其药学上可接受的盐；其中，所述式I化合物如权利要 求1中定义。
  12. 如权利要求11所述的方法，其特征在于，所述的TREK-1离子通道相关疾病为精神障碍类疾病。
  13. 如权利要求11所述的方法，其特征在于，所述的TREK-1离子通道相关疾病包括：抑郁症、焦虑症、精神分裂症、双向情感障碍、或其组合。
  14. 一种药盒，其特征在于，所述的药盒包括：
    (i)含式I化合物或其药学上可接受的盐作为活性成分的药物或制剂；和
    (ii)说明书。
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