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 medicines for diseases mediated by the mushroom type acetylcholine receptor.

Description

[0001] This application claims priority to the Chinese patent application No. CN202411562809.3, filed on November 5, 2024, with the State Intellectual Property Office, and entitled “A sulfonamide derivative and uses thereof”, the content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of medicinal chemistry, more particularly, to sulfonamide derivatives and uses thereof. BACKGROUND

[0003] Cholinergic neurotransmission involves activation of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) by binding of the endogenous agonist, acetylcholine (ACh), at orthosteric sites. Disorders associated with cognitive impairment, such as Alzheimer’s disease, are accompanied by a decrease in acetylcholine levels in the brain. This is thought to be a result of degeneration of cholinergic neurons in the basal forebrain, which widely innervate multiple regions of the brain, including the associative cortex and hippocampus, which are critically involved in higher processes. Clinical data support the notion that cholinergic hypofunction contributes to the cognitive deficits in patients with schizophrenia. Efforts to increase acetylcholine levels have focused on increasing levels of choline, a precursor to acetylcholine synthesis, and blocking acetylcholinesterase (AChE), an enzyme that metabolizes acetylcholine. As a result, acetylcholinesterase (AChE) inhibitors, which inhibit hydrolysis of ACh, have been approved in the United States for the palliative treatment of cognitive deficits in AD patients, but not for disease-modifying treatment.

[0004] Despite the progress in the study of muscarinic acetylcholine receptors, there is still a need to develop drugs having high activity effects on muscarinic acetylcholine receptor-mediated diseases. SUMMARY

[0005] In one aspect, the present disclosure relates to a compound of Formula I:

[0006]

[0007] wherein

[0008] R1is selected from C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6alkylhydroxy;

[0009] R2is selected from hydrogen, deuterium, halogen, cyano;

[0010] n = 2, 3 or 4;

[0011] R3is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6alkyl, C2-C6alkenyl.

[0012] In certain embodiments, R1is selected from C1-C3alkyl, C1-C3alkoxy, -CH=CH2, -CH2CF3, CD3, or C1-C3alkylhydroxyl.

[0013] In certain embodiments, R2is selected from halogen; preferably, R2is selected from fluorine or bromine, n = 2 or 3.

[0014] In certain embodiments, R3is selected from hydrogen, methyl, fluorine, bromine, -NH2, hydroxyl, or -CH=CH2.

[0015] In certain embodiments, Formula I is selected from the following compounds:

[0016]

[0017] In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt or a fumarate salt.

[0018] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0019] In yet another aspect, the present disclosure relates to a use in the manufacture of a medicament for treating and / or preventing a muscarinic acetylcholine receptor mediated disease, comprising administering to an individual in need of the method a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt, a deuterated derivative thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, a pharmaceutically acceptable salt, a deuterated derivative thereof.

[0020] The muscarinic acetylcholine receptor mediated disease is depression, manic depression, schizophrenia, autism, obsessive-compulsive disorder, anxiety, migraine, hypertension, eating disorder, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma, and overactive bladder.

[0021] The compounds of the present disclosure and compositions comprising the compounds of the present disclosure can be used in the manufacture of a medicament for treating and / or preventing a muscarinic acetylcholine receptor mediated disease. DETAILED DESCRIPTION

[0022] In the following description, certain specific details are included to provide a thorough understanding of various disclosed implementations. One skilled in the relevant art will recognize that implementations can be practiced without one or more of these specific details, or with other methods, components, materials, etc.

[0023] Unless otherwise required by context, the words "including," "comprising," and "having" shall be interpreted as meaning "including but not limited to."

[0024] As used in the specification and the appended claims herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0025] Reference throughout this specification to "an implementation" or "implementation" or "in another implementation" or "in certain implementations" means that a particular feature, structure, or characteristic being referred to is included in at least one implementation. Thus, appearances of the phrases "in one implementation" or "in an implementation" or "in another implementation" or "in certain implementations" in various places throughout the specification are not necessarily all referring to the same implementation. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more implementations.

[0026] It should be understood that the term "a" or "an" as used herein when used in the context of a "composition" or "structure" refers to one or more of the specified component, unless otherwise indicated. Thus, for example, a composition that is described as comprising "a pharmaceutically acceptable excipient" can comprise one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0027] Definitions

[0028] Certain chemical groups named herein are designated by a simplified symbol in front of the name of the chemical group that indicates the total number of carbon atoms found in the indicated chemical group. For example, C7-C12alkyl designates an alkyl group as defined below having a total number of carbon atoms from 7 to 12, and C4-C9cycloalkylalkyl designates a cycloalkylalkyl group as defined below having a total number of carbon atoms from 4 to 9. The total number of carbon atoms of a simplified symbol does not include carbon atoms that can be present in substituents of the named group. 12 Alkyl describes an alkyl group as defined below having a total number of carbon atoms from 1 to 12, and C1-C6alkyl describes an alkyl group as defined below having a total number of carbon atoms from 1 to 6. 12 Cycloalkylalkyl describes a cycloalkylalkyl group as defined below having a total number of carbon atoms from 4 to 12. The total number of carbon atoms of a simplified symbol does not include carbon atoms that can be present in substituents of the named group.

[0029] Therefore, the following terms as used in the specification and the appended claims, unless otherwise indicated, shall have the following meanings:

[0030] The term "cyano" as used herein means a -CN group.

[0031] The term "halogen" as used herein means fluorine, chlorine, bromine, or iodine.

[0032] As used in this disclosure, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, having 1 to 12 carbon atoms, and being connected to the rest of the molecule by single bonds. In some embodiments, the alkyl group has 1 to 8 carbon atoms. In some embodiments, the alkyl group has 1 to 6 carbon atoms. In some embodiments, the alkyl group has 1 to 4 carbon atoms. In some embodiments, exemplary examples of alkyl groups 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 some embodiments, the alkyl group may be optionally substituted, i.e., substituted or unsubstituted.

[0033] As used in this disclosure, the term "alkoxy" refers to the general formula -OR, where R is an alkyl group as defined above. In some embodiments, the alkoxy group has 1 to 8 carbon atoms. In some embodiments, the alkoxy group has 1 to 6 carbon atoms. In some embodiments, the alkoxy group has 1 to 4 carbon atoms. In some embodiments, exemplary 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 some embodiments, the alkoxy group may be optionally substituted, i.e., substituted or unsubstituted.

[0034] As used in this disclosure, the term "physiologically acceptable" refers to a carrier, diluent, or excipient that does not eliminate the biological activity and properties of the compound.

[0035] As used in this disclosure, the term "carrier" refers to a substance that enables the inclusion of a compound into a cell or tissue.

[0036] As used in this disclosure, the term "excipient" refers to an inert substance added to a pharmaceutical composition to provide (not limited to) bulk, consistency, stability, binding capacity, lubricity, and disintegration capacity of the composition.

[0037] As used in this disclosure, “pharmaceutical-acceptable carriers, diluents, or excipients” include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or animals and have no adverse effects on the composition of the pharmaceutical composition.

[0038] As used in this disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid adduct salt" and "acceptable base adduct salt".

[0039] As used in this disclosure, the term "pharmaceutical composition" refers to an formulation formed by the compound described in this disclosure and a medium generally accepted in the art for delivering a bioactive compound to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0040] As used in this disclosure, "therapeuticly effective amount" refers to the amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and its symptoms, or avoids or delays the onset of a particular disease or condition or its symptoms. The amount of the compounds described in this disclosure constituting a "therapeuticly effective amount" will vary depending on the compound, the disease state and its severity, and the age and weight of the mammal to be treated, but those skilled in the art can determine the amount of the compounds described in this disclosure conventionally based on their knowledge and this disclosure.

[0041] As used in this disclosure, "to treat" or "to treat" encompasses the treatment of a related disease or condition in mammals, such as humans, suffering from a related disease or ailment, and includes:

[0042] (i) To prevent the occurrence of disease or disease state in mammals, especially when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state;

[0043] (ii) Suppress the disease or disease state, that is, prevent it from occurring; or

[0044] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides or does not progress.

[0045] As used in this disclosure, the terms “disease” and “disease state” may be used interchangeably or may be different, because a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather as an undesirable disease state or symptom in which a clinician has identified a more or less specific set of symptoms.

[0046] Preservatives, stabilizers, dyes, sweeteners, flavorings, and fragrances can be provided in pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. Additionally, antioxidants and suspensions can be used.

[0047] In different implementation schemes, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, 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 oil, etc., can be used as suspensions or lubricants; cellulose acetate, as a derivative of sugars such as cellulose or sugar, or methyl acetate-isobutylene ester copolymer, as a derivative of polyethylene, can be used as suspensions; and plasticizers such as phthalates can be used as suspensions.

[0048] Suitable routes of administration may include, for example, oral, rectal, transmembrane, local, or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, or intraocular injection. Compounds can also be administered at a predetermined rate and / or timed, pulsatile manner in sustained-release or controlled-release dosage forms, including depot injections, osmotic pumps, pellets, and transdermal (including electromigration) patches.

[0049] The pharmaceutical compositions disclosed herein can be produced by known methods, such as conventional methods of mixing, dissolving, granulating, manufacturing tablets, grinding, emulsifying, encapsulating, retaining or compressing tablets.

[0050] Therefore, according to this disclosure, the pharmaceutical compositions used can be formulated using conventional methods with one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the treatment of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers, and excipients can be used as suitably understood and appreciated in the art.

[0051] Injectable formulations can be prepared in the following conventional forms: as solutions or suspensions, solid dosage forms suitable for preparation as solutions or suspensions prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. Additionally, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic excipients, 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 desired, absorption-enhancing agents (e.g., liposomes) may be used.

[0052] For transmembrane drug delivery, a permeabilizing agent suitable for permeability barriers may be used in the formulation.

[0053] Parenteral drug formulations, for example, administered by bolus or continuous infusion, include aqueous solutions of active compounds in water-soluble form. Alternatively, suspensions of the active compounds can be prepared as suitable oily injectable 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 injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compound to prepare high-concentration formulations. The injectable formulation and additional preservatives may be present in a single dosage form, such as in ampoules or multi-dose containers. The composition may be in an oily or aqueous carrier in a dosage form such as a suspension, solution, or emulsion, and the composition may contain agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier such as sterile pyrogen-free water before use.

[0054] For oral administration, the active compound can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such a carrier allows the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, ointments, suspensions, etc., for oral ingestion by a method in which the active compound is mixed with a solid excipient, the resulting mixture is ground in any manner, and the granulated mixture is processed, if necessary, with the addition of a suitable excipient to obtain a tablet or lozenge core. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginate or alginate such as sodium alginate may be added if necessary. The lozenge core is then appropriately coated. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or lozenge coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or lozenge coating.

[0055] Oral pharmaceutical formulations include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All oral formulations should be administered at a dose suitable for this administration.

[0056] For oral administration, the composition can be formulated into tablets or lozenges using conventional methods.

[0057] For inhalation administration, the compounds used in this disclosure are conveniently delivered in the form of 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 pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the metering amount. Capsules and cartridges, such as gelatin, used in inhalers or blowpipes can be formulated as powder mixtures containing the compound and a suitable powder matrix such as lactose or starch.

[0058] This disclosure also discloses a variety of pharmaceutical compositions known in the pharmaceutical industry for use in intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in a water-soluble form, such as eye drops, or in gellan gum or hydrogel form; ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymer particles suspended in a liquid carrier medium, lipid-soluble formulations, and microspheres; and ophthalmic inserts. For stability and comfort, these suitable pharmaceutical formulations are most often and preferably formulated as sterile, isotonic, and buffered pharmaceutical formulations. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, typically formulated to mimic nasal secretions in many ways to ensure maintenance of normal ciliary function. As is known to those skilled in the art, suitable formulations are most often and preferably isotonic, mildly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and suitable pharmaceutical stabilizers. Drug formulations for intraocular delivery include suspensions and ointments for topical application within the ear. Common solvents used in these ocular formulations include glycerin and water.

[0059] The compounds can also be formulated into rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0060] In addition to the aforementioned formulations, the compounds can also be formulated as reservoir-type formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, the compounds can be formulated, for example, using suitable polymers or hydrophobic materials (e.g., emulsions acceptable in oils) or ion exchange resins, or formulated as slightly soluble derivatives such as slightly soluble salts.

[0061] For hydrophobic compounds, a suitable drug carrier can 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 consists of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80™, and 65% w / v polyethylene glycol 300, with the volume made up by anhydrous ethanol. Of course, the proportions of the cosolvent system can be significantly altered without compromising its solubility and toxicity characteristics. Furthermore, the cosolvent components can be modified: for example, other low-toxicity nonpolar surfactants can be used instead of polysorbate 80™; the fragment size of polyethylene glycol can be altered; other biocompatible polymers such as polyvinylpyrrolidone can replace polyethylene glycol; and other sugars or polysaccharides can replace glucose.

[0062] Alternatively, other delivery systems for hydrophobic drug compounds can be used. Known examples of delivery media or carriers for hydrophobic drugs are liposomes and emulsions. While often at the cost of higher toxicity, certain organic solvents, such as dimethyl sulfoxide, can also be used. Additionally, sustained-release systems can be used to deliver compounds, such as semi-permeable matrices containing solid hydrophobic polymers of therapeutic drugs. Many sustained-release materials are known and established by those skilled in the art. Depending on their chemical properties, sustained-release capsules can release the compound over weeks to 100 days.

[0063] Reagents for intracellular drug delivery are administered using techniques known to those skilled in the art. For example, such reagents can be encapsulated in liposomes. During liposome formation, all molecules present in the aqueous solution are incorporated into the aqueous interior. The contents of the liposomes are not only unaffected by the external microenvironment, but are also efficiently delivered to the cytoplasm due to the fusion of the liposomes with the cell membrane. The liposomes can be coated with tissue-specific antibodies. The liposomes will be targeted to the desired organ and selectively absorbed by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.

[0064] Methods of administration

[0065] The compound or pharmaceutical composition may be administered to a patient by any suitable method. Non-limiting examples of administration methods include (a) oral administration, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) non-oral administration, such as rectal, vaginal, urethral, ​​intraocular, intranasal, or intraauricular administration, including administration in aqueous suspensions, oily preparations, or in drops, sprays, suppositories, ointments, creams, 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) localized administration, such as injection directly into the renal or cardiac region, for example, via a reservoir implant; and topically administration; as would be considered appropriate by those skilled in the art, the compound of the invention is in contact with living tissue.

[0066] 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 the recipient.

[0067] Suitable pharmaceutical compositions for administration include compositions containing an effective amount of the active ingredient to achieve their intended effect. The therapeutically effective dose of the pharmaceutical compositions disclosed in this invention depends on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent drug treatment, and other factors recognized by those skilled in the art. More specifically, a therapeutically effective dose refers to the amount of compound that effectively prevents, alleviates, or improves disease symptoms, or prolongs the lifespan of the treated individual. The therapeutically effective dose can be well determined by the practical ability of those skilled in the art, particularly according to the detailed disclosure provided in this invention.

[0068] As will be apparent to those skilled in the art, the dosage and specific route of administration for in vivo administration will vary depending on age, weight, the species of mammal being treated, the specific compound used, and the specific purpose of those compounds. Those skilled in the art can determine the effective dose level—the dose level necessary to determine the desired effect—using conventional pharmacological methods. Typically, human clinical application of a compound is initiated at a lower dose level, increasing the dose level until the desired effect is achieved. Alternatively, established pharmacological methods can be used to establish the effective dose and route of administration of the compositions identified by this method using acceptable in vitro studies.

[0069] In non-human animal studies, the application of a potential compound begins at a higher dose level and is gradually reduced until the desired effect is no longer achieved or adverse side effects disappear. The dose range can be broad, depending on the expected effect and therapeutic indication. Typically, the dose can range from about 10 μg / kg body weight to 500 mg / kg body weight, preferably from about 100 μg / kg body weight to 200 mg / kg body weight. Alternatively, as those skilled in the art will understand, the dose can be based on and calculated according to the patient's surface area.

[0070] Physicians can select the exact formulation, route of administration, and dosage of the pharmaceutical composition of the present invention based on the patient's condition. Typically, the dosage range of the composition administered to the patient can be from about 0.5 mg / kg to 1000 mg / kg of patient body weight. Depending on the patient's needs, the dosage can be given once, twice, or more frequently over a day or several days. Where the human dosage of the compound has been established under at least certain conditions, the present invention will use those same dosages, or dosage ranges from about 0.1% to 500% of the established human dosage, more preferably from 25% to 250% of the established human dosage. In cases where no established human dosage exists, such as in the case of a newly discovered pharmaceutical compound, a suitable human dosage can be determined from the ED... 50 or ID 50 The value, or other appropriate value derived from in vitro or in vivo studies, is inferred, as is quantified in toxicity studies and efficacy studies in animals.

[0071] It should be noted that, due to toxicity and organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust medication. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The dosage administered in the treatment of the condition of interest will vary depending on the severity of the disease state and the route of administration. For example, the severity of the disease state can be assessed in part using standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on the individual patient's age, weight, and response. Protocols equivalent to those discussed above can be used in veterinary medicine.

[0072] While an exact dosage can be determined based on drug-by-drug analysis, in most cases, some generalizations about the dosage can be made. Daily dosing regimens for adult patients include, for example, oral doses 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, intravenous, subcutaneous, or intramuscular doses of each active ingredient used are 0.01 mg to 1000 mg, preferably 0.1 mg to 800 mg, such as 1 to 200 mg. In the case of administering pharmaceutically acceptable saline, the dosage can be calculated based on free base. In some embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions of the invention can be administered by continuous intravenous infusion, preferably at doses up to 1000 mg of each active ingredient daily. As will be understood by those skilled in the art, in some situations, it is necessary to administer the compounds disclosed herein in amounts exceeding or far exceeding the preferred dosage ranges described above for effective and rapid treatment of rapidly progressing diseases or infections. In some embodiments, the compound is administered during continuous treatment, such as for one week or several weeks, or for several months or years.

[0073] Dosage and dosing intervals can be individually adjusted to provide plasma levels sufficient to maintain the modulated effect or minimum effective concentration (MEC) of the active moiety. The MEC varies for each compound, but it can be assessed from in vitro data. The required dose to achieve the MEC depends on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC or bioassays.

[0074] The MEC value can also be used to determine the dosing interval. The composition should be administered using a treatment regimen that 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.

[0075] In cases of local administration or selective absorption, the effective local concentration of a drug is independent of its plasma concentration.

[0076] Of course, the amount of the administered composition depends on the individual being treated, the individual's weight, the severity of their pain, the route of administration, and the prescribing physician's judgment.

[0077] The efficacy and toxicity of the compounds disclosed in this application can be evaluated using known methods. For example, the toxicology of a specific compound or a subset of compounds sharing certain chemical motifs can be established by determining the toxicity of cell lines, such as mammalian cell lines, and preferably human cell lines, in vitro. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, toxicity in humans. Alternatively, the toxicity of a specific compound in animal models such as mice, rats, rabbits, or monkeys 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. Recognized in vitro models exist for almost every type of disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. 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 efficacy, a person skilled in the art can choose an appropriate model, dosage, route of administration, and treatment regimen under the guidance of prior art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0078] If desired, the composition may be placed in a packaging or dispensing device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispensing device may include instructions for use. The packaging or dispensing device may also include precautions related to the container, provided by a government agency regulating the production, use, or sale of the drug, reflecting that the drug form has been approved by that agency for human or animal administration. Such precautions may, for example, be labels approved by the U.S. Food and Drug Administration for prescription drugs, or approved product instructions. Compositions containing the compounds of the present invention may also be prepared in suitable containers, formulated in compatible drug carriers, and labeled for the treatment of specified disease states.

[0079] Preparation of compounds

[0080] While any person skilled in the art can prepare the compounds of this application using the general techniques disclosed above, more detailed synthetic techniques for the compounds of this application are provided elsewhere in this specification for convenience. Furthermore, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and are available from common commercial sources. For example, various reagents used in the examples, including deuterated reagents, are available from Sigma-Aldrich Company Ltd.

[0081] Unless otherwise stated, 1¹H NMR is measured using deuterated dimethyl sulfoxide at a frequency of 500 MHz at approximately 20–30 °C. Standard NMR abbreviations are used: s = singlet; d = doublet; dd = doublet of doublet; t = triplet; q = quartet; p = quintet; m = multiplet; br = broadband.

[0082] Example 1 Preparation of 5-methoxy-1-(m-toluenesulfonyl)-2-(2,4,5-trifluorophenyl)-1H-imidazolium (Compound 1)

[0083]

[0084] (1) Synthesis of compound 1-C

[0085] Compound 1-A (440 mg) and compound 1-B (1 g) were mixed, and ammonia (25 mL) was added. The mixture was heated under reflux for 3 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 1-C in 67% yield.

[0086] (2) Synthesis of Compound 1

[0087] 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, 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%.

[0088] Example 2 Preparation of 5-ethyl-1-((3-fluorophenyl)sulfonyl)-2-(2,4,5-trifluorophenyl)-1H-imidazolium (compound 3)

[0089]

[0090] Referring to Example 1, 1-A was replaced with 3-A, and 3-methylbenzenesulfonyl chloride was replaced with 3-fluorobenzenesulfonyl chloride to prepare compound 3, with a yield of 30% to 40%.

[0091] Other compound synthesis methods are similar to those in Example 1, requiring only the replacement of the corresponding raw materials.

[0092]

[0093]

[0094] Biological Example 1

[0095] 1.1 Cell Culture

[0096] HT29 human colon cancer cells were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). HT29 cells were cultured in McCoy's 5A medium (GIBCO, catalog number 12800017, containing 4500.0 mg / L D-Glucose and 2.2 g / L NaHCO3) at 37°C in an incubator with 5% CO2 (air) at a volume concentration of 10% fetal bovine serum, 50 μg / mL ampicillin, and 100 μg / mL streptomycin sulfate.

[0097] 1.2 Experimental methods for the cellular activity of muscarinic M receptor antagonists

[0098] HT29 cells were seeded at a density of 2 × 10⁴ cells / well in 384-well biosensor microplates and incubated at 37°C in a 5% CO₂ (air) incubator for 22 h. Before detection, the cells were washed once with HBSS buffer, and then 30 μL of HBSS buffer was added to each well. The plates were then incubated on the system for equilibration for 1 h. After equilibration, a 2-minute baseline was established on the system. Then, 10 mL of hyoscyamine and scopolamine (each compound had 14 concentration points, with a maximum working concentration of 10 μM, serially diluted 2-fold to 5 μM, 2.5 μM, 1.25 μM, etc.) were added to the HT29 cell-seeded 384-well biosensor microplates to determine the antagonistic activity of the compounds against muscarinic M receptors.

[0099] Absorbance readings for each well were collected using SoftMaxPro software and imported into a Microsoft Excel spreadsheet for further calculations. Outliers were detected using the Grubbs test built into Graphpad Prism 9. For each well, the percentage viral reduction (PVR) was calculated using a formula, and the half-maximal inhibitory concentration (EC50) was calculated by fitting a concentration-response curve to each sample using a 4-parameter nonlinear regression curve. 50 ).

[0100] Compound numbers EC 50 (nM) 1 12 2 45 3 10 4 37 5 35 6 21 7 13 8 11 9 655

[0101] The above are merely preferred embodiments of the present invention and do not constitute any limitation on the present invention. Any equivalent substitutions or modifications made by those skilled in the art to the technical solutions and content disclosed in the present invention without departing from the scope of the present invention are considered to have remained within the protection scope of the present invention.

Claims

1. The 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 alkylhydroxy; R2 is selected from any one of hydrogen, deuterium, halogen, and cyano groups; 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 of 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 of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from halogens.

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

5. The compound of 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 of 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 any compound of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and treatment of diseases mediated by muscarinic acetylcholine receptors.

9. The use as described in claim 8, wherein the muscarinic acetylcholine receptor-mediated disease is any one of depression, bipolar disorder, schizophrenia, autism, obsessive-compulsive neurosis, anxiety disorder, migraine, hypertension, eating disorder, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma, and overactive bladder.

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