Sulfonyl derivative and application

Abstract

The invention relates to the field of medicinal chemistry, and discloses a sulfonyl derivative as well as a preparation method and application thereof. The compound provided by the invention and the composition containing the compound provided by the invention can be used for preparing drugs for 5-HT receptor mediated diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and more particularly to sulfonyl derivatives and uses thereof. Background Art

[0002] 5-HT is a type of serotonin and an important neurotransmitter. 5-HT receptors mediate the effects of serotonin in the nervous system and other tissues, playing a variety of physiological functions such as regulating emotions, cognition, and sleep. These receptors can be divided into multiple subtypes, including 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Different 5-HT receptors produce different biological effects. For example, the 5-HT1 receptor subtype mainly inhibits neurotransmission, including inhibiting the activity of adenylate cyclase and inhibiting depolarizing potassium channels, while the 5-HT2 receptor subtype mainly excites neurotransmission, including activating the phosphatidylinositol signaling pathway and increasing the activity of adenylate cyclase.

[0003] Serotonin receptors play an important role in the central nervous system. For example, 5-HT1A receptors play an important role in regulating emotions, anxiety and depression; 5-HT2A receptors are involved in regulating learning and memory; 5-HT3 receptors are involved in vomiting reactions, etc. In addition, serotonin receptors are also present in other tissues, such as the digestive system, cardiovascular system, and immune system. In these tissues, they participate in regulating physiological processes such as gastrointestinal motility, blood pressure regulation, and immune response.

[0004] In summary, the activation and inhibition of serotonin receptors are crucial for regulating the function of the neurotransmitter serotonin, and they mediate the effects of serotonin in different tissues and organs through a variety of signal transduction mechanisms. The study of these receptors and their signaling pathways provides potential targets for the development of new drugs to treat various diseases.

[0005] In order to prevent and treat diseases related to 5-HT, it is necessary to study compounds that can exhibit its inhibitory effect. Summary of the invention

[0006] In one aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in

[0009] R1 is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, and C1-C6 alkylhydroxyl;

[0010] R2 is selected from any one of hydrogen, deuterium, halogen, and cyano;

[0011] n = 2, 3 or 4;

[0012] R3 is selected from any one of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl and C2-C6 alkenyl.

[0013] In certain embodiments, R1 is selected from C1-C3 alkyl, C1-C3 alkoxy, -CH=CH2, -CH2CF3, CD3 or C1-C3 alkylhydroxy.

[0014] In certain embodiments, R2 is selected from halogen; preferably, R2 is selected from fluorine or bromine, and n=2 or 3.

[0015] In certain embodiments, R3 is selected from hydrogen, methyl, fluoro, bromo, -NH2, hydroxyl, or -CH=CH2.

[0016] In certain embodiments, Formula I is selected from the following compounds:

[0017]

[0018] In certain embodiments, the pharmaceutically acceptable salt is hydrochloride or fumarate.

[0019] On the other hand, a pharmaceutical composition is also provided, comprising at least any one of the above compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0020] In another aspect, the present disclosure relates to a method for preparing a drug for treating and / or preventing 5-HT receptor-mediated diseases, comprising administering a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt or a deuterated substance thereof to an individual in need of the method, or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I, a pharmaceutically acceptable salt or a deuterated substance thereof.

[0021] The 5-HT receptor mediated diseases are depression, manic depression, schizophrenia, autism, obsessive compulsive disorder, anxiety, migraine, hypertension, eating disorders, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma and overactive bladder.

[0022] The present invention also provides a deuterated substance of any of the above compounds or a pharmaceutically acceptable salt thereof.

[0023] The compound proposed by the present invention and the composition containing the compound proposed by the present invention can be used to prepare drugs for diseases mediated by 5-HT receptors. DETAILED DESCRIPTION

[0024] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details, but with other methods, components, materials, etc.

[0025] Unless otherwise required by the present disclosure, throughout the specification and claims that follow, the words "including" and "comprising" should be interpreted in an open, inclusive sense, ie, "including, but not limited to."

[0026] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0027] References to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" throughout this specification are intended to include in at least one embodiment the specific referenced elements, structures or features described in connection with that embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, the specific elements, structures or features may be combined in any appropriate manner in one or more embodiments.

[0028] It should be understood that the singular article "a", "an" and "the" used in the specification of the present disclosure and the appended claims include plural objects unless the context clearly stipulates otherwise. Therefore, for example, a sustained-release tablet containing "pharmaceutically acceptable excipients" is included in one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0029] definition

[0030] Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms found in the chemical group shown. 12 Alkyl describes an alkyl group as defined below having a total of 7 to 12 carbon atoms, and C4-C 12 Cycloalkylalkyl describes a cycloalkylalkyl group as defined below having a total of 4 to 12 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0031] Therefore, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0032] The term "cyano" as used in this disclosure refers to a -CN group.

[0033] The term "halogen" as used in this disclosure refers to fluorine, chlorine, bromine or iodine.

[0034] The term "alkyl" used in the present disclosure refers to a straight or branched hydrocarbon chain group, consisting only of carbon and hydrogen atoms, does not contain unsaturated bonds, has 1 to 12 carbon atoms, and is connected to the rest of the molecule by a single bond. In certain embodiments, the alkyl has 1 to 8 carbon atoms. In certain embodiments, the alkyl has 1 to 6 carbon atoms. In certain embodiments, the alkyl has 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkyl include but are not limited to methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. In certain embodiments, the alkyl can be optionally substituted, i.e., substituted or unsubstituted.

[0035] The term "alkoxy" used in the present disclosure refers to the general formula -OR, wherein R is an alkyl group as defined above. In certain embodiments, the alkoxy group has 1 to 8 carbon atoms. In certain embodiments, the alkoxy group has 1 to 6 carbon atoms. In certain embodiments, the alkoxy group has 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, tert-pentoxy, etc. In certain embodiments, the alkoxy group can be optionally substituted, i.e., substituted or unsubstituted.

[0036] As used in this disclosure, the term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

[0037] The term "vector" as used in this disclosure refers to a substance that enables the incorporation of a compound into cells or tissues.

[0038] The term "excipient" as used in the present disclosure refers to an inert substance added to a pharmaceutical composition to provide (without limitation) bulk, consistency, stability, binding capacity, lubricity, disintegration ability, etc. to the composition.

[0039] The "pharmaceutically acceptable carrier, diluent or excipient" used in the present disclosure includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0040] The term "pharmaceutically acceptable salt" used in the present disclosure includes "acceptable acid addition salts" and "acceptable base addition salts".

[0041] The term "pharmaceutical composition" used in the present disclosure refers to a preparation of the compounds described in the present disclosure and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0042] As used in the present disclosure, "therapeutically effective amount" refers to the amount of a compound or combination of compounds that improves, attenuates or eliminates a particular disease or condition and the symptoms of a particular disease or condition, or avoids or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition. The amount of the compound described in the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but those skilled in the art can determine the amount of the compound described in the present disclosure according to routine based on their own knowledge and the present disclosure.

[0043] As used in this disclosure, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, that suffers from the relevant disease or condition, and includes:

[0044] (i) preventing a disease or disease state from occurring in a mammal, particularly where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state;

[0045] (ii) inhibit the disease or disease state, i.e. prevent its occurrence; or

[0046] (iii) ameliorating a disease or condition, even if the disease or condition regresses or does not progress.

[0047] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific set of symptoms.

[0048] Preservatives, stabilizers, dyes, sweeteners, aromatics, spices, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used.

[0049] In different embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethylcellulose calcium, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as suspending agents; and plasticizers such as phthalates can be used as suspending agents.

[0050] Suitable routes of administration may include, for example, oral administration, rectal administration, transmembrane administration, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compound can also be extended and / or timed, pulsed administration at a predetermined rate in a sustained-release or controlled-release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc.

[0051] The pharmaceutical composition of the present disclosure can be produced in a known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or tableting operations.

[0052] Therefore according to the present disclosure, the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically available preparation. Suitable preparations depend on the selected route of administration. Any known technology, carrier and excipient can be used as suitable and understood in the art.

[0053] Injection can be prepared into the following conventional forms: as a solution or suspension, a solid dosage form suitable for making a solution or suspension before injection, or as an emulsion. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.

[0054] For transmembrane administration, penetrants appropriate to the barrier to be permeated are used in the formulation.

[0055] Pharmaceutical preparations for parenteral administration, for example, by push injection or continuous infusion, include aqueous solutions of active compounds in water-soluble form. In addition, suspensions of active compounds can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium hydroxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compound to prepare high-concentration preparations. Injection preparations and additional preservatives may be present in unit dosage form, for example in ampoules or multidose containers. The composition may be in an oily or aqueous vehicle in a dosage form such as a suspension, solution or emulsion, and the composition may contain agents such as a suspending agent, a stabilizer and / or a dispersant. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0056] For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture and processing the granular mixture, if necessary, after adding suitable auxiliary agents to obtain tablets or lozenge cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate may be added if necessary. The lozenge cores are suitably coated. For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally include gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel (8arbopol gel), polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to identify or characterize the different combinations of active compound dosage, dyestuff or pigment can be added in tablet or lozenge coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally include gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to identify or characterize the different combinations of active compound dosage, dyestuff or pigment can be added in tablet or lozenge coating.

[0057] Pharmaceutical preparations that can be used for oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0058] For oral administration, the composition may be formulated in the form of tablets or lozenges according to conventional methods.

[0059] For administration by inhalation, the compounds for use in the present disclosure are conveniently delivered as a spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Capsules and cartridges such as gelatin for use in an inhaler or insufflator may be formulated as a powder mix comprising the compound and a suitable powder base such as lactose or starch.

[0060] The present disclosure also discloses a variety of pharmaceutical compositions known in the pharmaceutical field for delivery including intraocular, intranasal and intraauricular. Penetrants suitable for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of active compounds in water-soluble form, such as eye drops, or in the form of gellan gum or hydrogel; ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymer particles suspended in a liquid carrier medium, lipid-soluble preparations and microspheres; and ophthalmic inserts. For stability and comfort, these suitable pharmaceutical preparations are most often and preferably formulated as sterile, isotonic and buffered pharmaceutical preparations. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are usually prepared to simulate nasal secretions in many aspects to ensure that normal ciliary action is maintained. As is well known to those skilled in the art, suitable preparations are most often and preferably isotonic, lightly buffered to maintain the pH at 5.5 to 6.5, and they most often and preferably include antimicrobial preservatives and suitable drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such otic preparations include glycerol and water.

[0061] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0062] In addition to the aforementioned preparations, the compound can also be formulated as a reservoir preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound can be formulated using a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative such as a slightly soluble salt.

[0063] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant polysorbate 80™, and 65% w / v of polyethylene glycol 300 made up to volume by anhydrous ethanol. Of course, the proportions of the cosolvent system may be varied considerably without destroying its solubility and toxicity characteristics. In addition, the cosolvent components may be varied: for example, other low-toxic nonpolar surfactants may be used in place of polysorbate 80™; the fragment size of polyethylene glycol may be varied; other biocompatible polymers such as polyvinyl pyrrolidone may be substituted for polyethylene glycol; and other sugars or polysaccharides may be substituted for glucose.

[0064] Alternatively, other delivery systems of hydrophobic drug compounds can be used. Known examples of delivery media or carriers of hydrophobic drugs are liposomes and emulsions. Although usually at the expense of higher toxicity, some organic solvents, such as dimethyl sulfoxide, can also be used. In addition, sustained-release systems can be used to deliver compounds, such as semipermeable matrices of solid hydrophobic polymers that comprise therapeutic drugs. Many sustained-release materials are known and established by those skilled in the art. According to its chemical properties, sustained-release capsules can release the compound in a few weeks to 100 days.

[0065] The reagent for intracellular administration is given using techniques known to those of ordinary skill in the art. For example, this type of reagent can be encapsulated into liposomes. When forming liposomes, all molecules present in the aqueous solution are incorporated into the aqueous interior. The inclusions of the liposomes are not only not affected by the external microenvironment, but also because the liposomes merge with the cell membrane, the inclusions are effectively transported to the cytoplasm. Liposomes can be coated with tissue-specific antibodies. Liposomes will be targeted to the desired organ and selectively absorbed by the desired organ. Alternatively, small hydrophobic organic molecules can be given directly into the cell.

[0066] Dosage

[0067] The compound or pharmaceutical composition can be administered to the patient by any suitable method. Non-limiting examples of administration methods include (a) administration by oral route, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) administration by non-oral route, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraauricular, including administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) local administration such as injection directly in the kidney area or heart area, for example, by reservoir implantation; and I local administration; as considered by those skilled in the art, the appropriate mode of administration is contact of the compound of the present invention with living tissue.

[0068] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients and other matters related to delivering the compound to a subject in need.

[0069] Pharmaceutical compositions suitable for administration include compositions containing an effective amount of active ingredients to achieve their desired effects. The dosage required for the therapeutically effective amount of the pharmaceutical compositions disclosed in the present invention depends on the route of administration, the type of animal to be treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect, but this will depend on the following factors: body weight, diet, simultaneous drug therapy, and other factors recognized by technicians in other medical fields. More specifically, the therapeutically effective amount refers to the amount of the compound that effectively prevents, alleviates or improves the symptoms of the disease, or prolongs the life span of the individual receiving treatment. The actual ability of those skilled in the art can well determine the therapeutically effective amount, particularly in accordance with the detailed disclosure provided by the present invention.

[0070] As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the specific compound being used, and the specific purpose of the compound being used. The purpose of determining the effective dosage level, i.e., the dosage level necessary for the desired effect, can be achieved by those skilled in the art using conventional pharmacological methods. Typically, clinical use of the compound in humans is initiated at a lower dosage level, with the dosage level increasing until the desired effect is achieved. Alternatively, using established pharmacological methods, an effective dosage and route of administration of the composition identified by the present method can be established using acceptable in vitro studies.

[0071] In non-human animal studies, the use of potential compounds is started at a higher dose level, with the dose reduced until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the therapeutic indication, the dosage range can be relatively wide. Generally, the dosage can be about 10 μg / kg body weight to 500 mg / kg body weight, preferably about 100 μg / kg body weight to 200 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage can be based on the surface area of ​​the patient and calculated accordingly.

[0072] Each physician will be able to select the exact formulation, route of administration, and dosage of the pharmaceutical compositions of the present invention based on the patient's condition. Typically, the dosage range of the composition administered to the patient may be about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. The dosage may be administered once alone or twice or more during a day or several days, depending on the patient's needs. In cases where human dosages for compounds have been established due to at least certain conditions, the present invention will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosages, with a more preferred dosage range of 25% to 250% of the established human dosages. In the absence of an established human dosage, such as in the case of a newly discovered drug compound, a suitable human dosage can be obtained from ED 50 or ID 50 Values, or other appropriate values ​​from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.

[0073] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the dosage in the treatment of the disease concerned will vary with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by standard prognostic evaluation methods. In addition, the dosage and possible dosage frequency will also vary according to the age, weight, and response of the individual patient. A scheme comparable to the above-mentioned discussion scheme can be used in veterinary medicine.

[0074] Although the exact dosage can be determined on a drug-by-drug basis, in most cases, certain generalizations can be made about the dosage. The daily dosage regimen for adult patients is, for example, an oral dosage of 0.1 mg to 2000 mg of each active ingredient, preferably 1 mg to 1000 mg of each active ingredient, such as 5 to 500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dosage of each active ingredient used is 0.01 mg to 1000 mg, preferably 0.1 mg to 800 mg, such as 1 to 200 mg. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as a free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the composition of the present invention can be administered by continuous intravenous infusion, preferably at a dosage of up to 1000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain cases, it is necessary to administer the compounds disclosed herein in an amount exceeding or far exceeding the above-mentioned preferred dosage range in order to effectively and rapidly treat rapidly developing diseases or infections. In certain embodiments, the compound is administered over a continuous treatment period, such as for one or more weeks, or months or years.

[0075] Dosage and dosing interval can be adjusted individually to provide the plasma level of the active part that is enough to maintain the adjustment effect or minimum effective concentration (MEC). The MEC of each compound is different, but MEC can be estimated from in vitro data. The required dosage reaching MEC depends on individual characteristics and route of administration. However, HPLC determination or bioassay can be used to determine plasma concentration.

[0076] The MEC value also enables determination of dosing intervals.Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time, and more preferably 50-90% of the time.

[0077] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0078] The amount of composition administered will, of course, be dependent upon the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0079] The efficacy and toxicity of the compounds disclosed in the present application can be evaluated using known methods. For example, the toxicology of a specific compound or a subset of the compounds that share certain chemical moieties can be established by determining the toxicity of a cell line in vitro, such as a mammalian cell line and preferably a human cell line. The results of such studies can generally predict the toxicity in an animal such as a mammal, or more specifically, the toxicity in a human. Alternatively, the toxicity of a specific compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods. The efficacy of a specific compound can be determined using several recognized methods, such as in vitro methods, animal models or human clinical trials. There are recognized in vitro models for almost every disease state, including but not limited to cancer, cardiovascular disease and a variety of immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemical drugs for treating these disease states. When selecting a model to determine the efficacy, the technician can select an appropriate model, dosage and route of administration, and treatment regimen under the guidance of the prior art in the art. Of course, human clinical trials can also be used to determine the efficacy of compounds in humans.

[0080] If desired, the composition can be placed in a package or dispensing device, which can contain one or more unit dosage forms containing active ingredients. The package can, for example, include metal or plastic foil, such as a blister package. The package or dispensing device can carry instructions for administration. The package or dispensing device can also carry precautions associated with the container, which are prescribed by a government agency that manages drug production, use or sales, and which reflect that the drug form has been approved by the agency for human or veterinary administration. Such precautions, for example, can be labels approved by the U.S. Food and Drug Administration for prescription drugs, or approved product instructions. Compositions comprising the compounds of the present invention that are formulated in a compatible pharmaceutical carrier can also be prepared in a suitable container and labeled for use in the treatment of a specified disease state.

[0081] Preparation of compounds

[0082] Although any person skilled in the art can prepare the compounds of the present application according to the general techniques disclosed above, for convenience, more detailed synthesis techniques of the compounds of the present application are provided elsewhere in this specification. In addition, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and can be obtained from common commercial sources. For example, various reagents including deuterated reagents used in the examples can be purchased from Sigma-Aldrich Company Ltd.

[0083] Unless otherwise stated, 1HNMR was measured using deuterated dimethyl sulfoxide at 500 MHz at about 20-30° C. Standard NMR abbreviations are used: s = singlet; d = doublet; dd = doublet of a doublet; t = triplet; q = quartet; p = quintet; m = multiplet; br = broad band.

[0084] Example 1 Preparation of 5-methoxy-1-(m-toluenesulfonyl)-2-(2,4,5-trifluorophenyl)-1H-imidazole (Compound 1)

[0085]

[0086] (1) Synthesis of Compound 1-C

[0087] Compound 1-A (440 mg) and compound 1-B (1 g) were mixed, and aqueous ammonia (25 mL) was added, and the mixture was heated under reflux for 3 h. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 1-C with a yield of 67%.

[0088] (2) Synthesis of Compound 1

[0089] At 0°C, compound 1-C (780 mg) and 3-methylbenzenesulfonyl chloride were mixed, and N,N-diisopropylethylamine (DIPEA) (6 mL) was added dropwise. The mixture was stirred at 0°C for 3 h, and extracted with ethyl acetate (10 mL×5). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain compound 1 with a yield of 43%.

[0090] Example 2 Preparation of 5-ethyl-1-((3-fluorophenyl)sulfonyl)-2-(2,4,5-trifluorophenyl)-1H-imidazole (Compound 3)

[0091]

[0092] Referring to Example 1, 1-A was replaced by 3-A, and 3-methylbenzenesulfonyl chloride was replaced by 3-fluorobenzenesulfonyl chloride to prepare compound 3 with a yield of 30% to 40%.

[0093] The synthesis methods of other compounds are similar to those in Preparation Example 1, except that the corresponding raw materials need only be replaced.

[0094]

[0095]

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[0098] Biological Example 1

[0099] 1.1 Cell culture

[0100] HT29 human colon cancer cells were obtained from the Cell Bank of the Chinese Academy of Sciences Type Culture Collection Committee (Shanghai, China). HT29 cells were cultured in a 37°C, 5% CO2 (air) incubator in a 10% volume concentration of fetal bovine serum, 50 μg / ml ampicillin, 100 μg / mL streptomycin sulfate McCoy's 5A medium (GIBCO, Cat. No. 12800017, containing 4500.0 mg / L D-Glucose and 2.2 g / L NaHCO3).

[0101] 1.2 Cellular activity assay of 5-HT receptor antagonists

[0102] HT29 cells were seeded into 384-well biosensor microplates at a density of 2×104 cells / well, and cultured in an incubator at 37°C and 5% CO2 (air) by volume for 22 hours. The cells were washed once with HBSS buffer before detection, and then 30 μL HBSS buffer was added to each well, and the cells were placed on the system for 1 hour of equilibrium incubation. After equilibrium, a 2-min baseline was first established on the system, and then 10 mL of hyoscyamine and scopolamine (each compound had 14 concentration points, the highest working concentration was 10 μM, 2-fold serial dilution, 5 μM, 2.5 μM, 1.25 μM, etc.) were added to the 384-well biosensor microplates seeded with HT29 cells to determine the antagonistic activity of the compounds against muscarinic M receptors.

[0103] The absorbance readings for each well were collected by SoftMaxPro software and imported into a Microsoft Excel spreadsheet for further calculations. Outliers were detected by the built-in Grubbs test in Graphpad Prism 9. For each well, the percent viral reduction (PVR) was calculated using the formula, and the half inhibitory concentration (EC) was calculated by fitting the concentration-response curve of each test article by a 4-parameter nonlinear regression curve. 50 ).

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[0105]

[0106] The above is only a preferred embodiment of the present invention and does not have any limiting effect on the present invention. Any technician in the relevant technical field, without departing from the scope of the technical solution of the present invention, makes any equivalent replacement or modification to the technical solution and technical content disclosed in the present invention, which is within the scope of the technical solution of the present invention and still within the protection scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, and C1-C6 alkylhydroxyl; R2 is selected from any one of hydrogen, deuterium, halogen, and cyano; n = 2, 3 or 4; R3 is selected from any one of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl and C2-C6 alkenyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from any one of C1-C3 alkyl, C1-C3 alkoxy, -CH=CH2, -CH2CF3, CD3 and C1-C3 alkylhydroxy.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from halogen.

4. The compound or pharmaceutically acceptable salt according to claim 3, wherein R2 is selected from fluorine or bromine, and n=2 or 3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from any one of hydrogen, methyl, fluorine, bromine, -NH2, hydroxyl and -CH=CH2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following compounds:

7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and treating diseases mediated by 5-HT receptors.

9. The use according to claim 8, wherein the 5-HT receptor-mediated disease is any one of depression, manic depression, schizophrenia, autism, obsessive-compulsive disorder, anxiety, migraine, hypertension, eating disorders, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma and overactive bladder.

10. A deuterated substance of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

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