CN119409641A - Sulfonyl derivative and application thereof - Google Patents

Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses a sulfonyl derivative, a preparation method and application thereof. The compounds and compositions comprising the compounds of the present invention are useful in the preparation of medicaments for 5-HT receptor mediated diseases.

Description

Sulfonyl derivative and application thereof

Technical Field

The present invention relates to the field of pharmaceutical chemistry, more specifically to sulfonyl derivatives and their use.

Background

5-Hydroxytryptamine (5-HT) is a serotonin and is also an important neurotransmitter. The 5-HT receptor mediates the effect of serotonin in nervous system and other tissues, and plays a role in regulating emotion, cognition, sleep and other physiological functions. 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 primarily inhibits neurotransmission, including inhibition of adenylate cyclase activity, inhibition of depolarized potassium channels, etc., while the 5-HT2 receptor subtype primarily excites neurotransmission, including activation of phosphatidylinositol signaling pathways, increase of adenylate cyclase activity, etc.

Serotonin receptors play an important role in the central nervous system. For example, 5-HT1A receptors have important roles in regulating emotion, anxiety and depression, 5-HT2A receptors are involved in regulating learning and memory, 5-HT3 receptors are involved in vomiting response, etc. Furthermore, serotonin receptors are also present in other tissues, such as the digestive system, cardiovascular system, and immune system. They are involved in these tissues in regulating physiological processes such as gastrointestinal motility, blood pressure regulation and immune response.

In summary, activation and inhibition of serotonin receptors are critical for the functional regulation of the neurotransmitter serotonin, which mediates the actions of serotonin in different tissues and organs through a variety of signaling mechanisms. The study of these receptors and their signaling pathways provides potential targets for the development of new drugs for the treatment of various diseases.

In order to prevent and treat 5-HT-related diseases, it is necessary to study compounds capable of exhibiting an inhibitory effect thereon.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I):

wherein the method comprises the steps of

R ₁ is selected from any one of C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₂-C₆ alkenyl, C ₁-C₆ haloalkyl, C ₁-C₆ deuterated alkyl and C ₁-C₆ alkyl hydroxy;

R ₂ is selected from any one of hydrogen, deuterium, halogen and cyano;

n=2, 3 or 4;

R ₃ is selected from any one of hydrogen, deuterium, halogen, cyano, hydroxy, amino, C ₁-C₆ alkyl and C ₂-C₆ alkenyl.

In certain embodiments, R ₁ is selected from C ₁-C₃ alkyl, C ₁-C₃ alkoxy, -ch=ch ₂、-CH₂CF₃、CD₃, or C ₁-C₃ alkyl hydroxy.

In certain embodiments, R ₂ is selected from halogen, preferably R ₂ is selected from fluorine or bromine, n=2 or 3.

In certain embodiments, R ₃ is selected from hydrogen, methyl, fluoro, bromo, -NH ₂, hydroxy, or-ch=ch ₂.

In certain embodiments, formula I is selected from the following compounds:

in certain embodiments, the pharmaceutically acceptable salt is a hydrochloride or fumarate salt.

In another aspect, there is also provided a pharmaceutical composition comprising at least any one of the compounds described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present disclosure relates to a method of treating and/or preventing a 5-HT receptor mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, a deuteride, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, a deuteride.

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 ulcers, diabetic neuropathy, asthma and overactive bladder.

The invention also provides deuterated compounds of any of the above compounds or pharmaceutically acceptable salts thereof.

The compounds and compositions comprising the compounds of the present invention are useful in the preparation of medicaments for 5-HT receptor mediated diseases.

Detailed Description

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

Throughout the specification and claims which follow, unless the context requires otherwise, the words "comprise" and "comprising" are to be construed in an open-ended, inclusive sense, i.e. "including but not limited to.

As used in this disclosure and the appended claims, the singular reference without a quantitative indication includes the plural reference unless the context clearly dictates otherwise.

Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure, or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in the specification of this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a sustained release tablet comprising "pharmaceutically acceptable excipients" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

Definition of the definition

Certain chemical groups named herein are identified previously by simplified symbols indicating the total number of carbon atoms found in the chemical groups shown. For example, C ₇-C₁₂ alkyl describes an alkyl group as defined below having a total of 7 to 12 carbon atoms, and C ₄-C₁₂ cycloalkyl alkyl describes a cycloalkyl alkyl group as defined below having a total of 4 to 12 carbon atoms. The total number of carbon atoms in the reduced symbol does not include carbon that may be present in a substituent of the group.

Accordingly, the following terms, as used in the specification and the appended claims, shall have the following meanings:

the term "cyano" as used in this disclosure refers to a-CN group.

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

The term "alkyl" as used in this disclosure refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, and which is attached to the remainder of the molecule by a single bond. In certain embodiments, the alkyl groups have 1 to 8 carbon atoms. In certain embodiments, the alkyl groups have 1 to 6 carbon atoms. In certain embodiments, the alkyl groups have 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. In certain embodiments, the alkyl group may be optionally substituted, i.e., substituted or unsubstituted.

The term "alkoxy" as used in this disclosure refers to the general formula-OR, wherein R is an alkyl group as defined above. In certain embodiments, the alkoxy groups have 1 to 8 carbon atoms. In certain embodiments, the alkoxy groups have 1 to 6 carbon atoms. In certain embodiments, the alkoxy groups have 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, pentyloxy, tert-pentyloxy, and the like. In certain embodiments, the alkoxy group may be optionally substituted, i.e., substituted or unsubstituted.

The term "physiologically acceptable" as used in this disclosure defines a carrier, diluent or excipient that does not negate the biological activity and properties of the compound.

The term "carrier" as used in this disclosure refers to a substance that effects incorporation of a compound into a cell or tissue.

The term "excipient" as used in this disclosure refers to an inert substance added to a pharmaceutical composition that provides (without limitation) bulk (bulk), consistency, stability, binding ability, lubricity, and disintegration ability, etc. to the composition.

As used herein, "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, and the like that have been approved by the U.S. food and drug administration for use in humans or animals.

The term "pharmaceutically acceptable salt" as used in this disclosure includes "acceptable acid addition salts" and "acceptable base addition salts".

The term "pharmaceutical composition" as used in this disclosure refers to a formulation of a compound described in this disclosure with a medium that delivers a biologically active compound to a mammal, such as a human, as is commonly accepted in the art. Such vehicles include all pharmaceutically acceptable carriers, diluents or excipients.

As used herein, a "therapeutically effective amount" refers to an amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or avoids or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of a compound described in this disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age, weight, etc., of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.

As used herein, "treating" or "treatment" encompasses treatment-related diseases or disease states in a mammal, such as a human, having a related disease or disorder, and includes:

(i) Preventing a disease or a disease state from occurring in a mammal, particularly when the mammal is susceptible to the disease state, but has not been diagnosed with the disease state;

(ii) Inhibiting the disease or condition, i.e. preventing it from occurring, or

(Iii) The disease or disease state is alleviated even if the disease or disease state regresses or does not progress.

As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably or may be different in that a particular disease or disease state may not have known causative agents (and therefore cannot be interpreted by etiology) and therefore is not recognized as a disease, but rather is considered an undesired disease state or condition in which a clinician has identified more or less of a particular set of symptoms.

Preservatives, stabilizers, dyes, sweeteners, fragrances, perfumes and the like may be provided in the pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of parahydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspensions may be used.

In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants, sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, methyl magnesium aluminate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethyl cellulose calcium, and the like may be used as excipients, magnesium stearate, talc, hardened oil, and the like may be used as a smoothing agent, coconut oil, olive oil, sesame oil, peanut oil, soybean, and the like may be used as a suspension or lubricant, cellulose acetate, as derivatives of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymers, as derivatives of polyethylene, may be used as a suspension, and plasticizers such as phthalate, and the like may be used as a suspension.

Suitable routes of administration may include, for example, oral, rectal, transdermal, topical or enteral administration, parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection. The compounds can also be administered at a predetermined rate and/or at a predetermined timing, in sustained or controlled release dosage forms including depot injections (depotinjections), osmotic pumps, pills, transdermal (including electrotransport) patches, and the like.

The pharmaceutical compositions of the present disclosure may be produced in known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting procedures.

Thus, in accordance with the present disclosure, the pharmaceutical compositions employed may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the route of administration selected. Any known techniques, carriers and excipients may be used as appropriate and understood in the art.

The injection can be prepared in conventional form as a solution or suspension, a solid dosage form suitable for preparation of a solution or suspension prior to injection, or as an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if desired, the injectable pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffers and the like. 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.

For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.

Pharmaceutical formulations for parenteral administration, for example, by bolus injection or continuous infusion, comprise aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles 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, for example sodium hydroxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compounds to produce high concentration formulations. The injectable preparation and the additional preservative may be present in unit dosage form, for example, in ampoules or in multi-dose containers. The composition may take such dosage forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and the composition may contain agents such as suspensions, stabilizing and/or dispersing agents. Or the active ingredient may be in powder form for reconstitution with a suitable carrier, such as sterile pyrogen-free water, prior to use.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. For oral ingestion by a patient to be treated, such carriers enable the compounds of the invention to be formulated as tablets, pills, troches, capsules, liquids, gels, syrups, slurries, suspensions and the like. Pharmaceutical formulations for oral administration can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, if desired after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients include, 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, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, for example crosslinked polyvinylpyrrolidone, agar or alginic acid or an alginate such as sodium alginate. The lozenge cores are suitably coated. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel (8 arbopol gel), polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound doses, dyes or pigments may be added to the tablet or lozenge coating. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound doses, dyes or pigments may be added to the tablet or lozenge coating.

Pharmaceutical formulations that can be used for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, such as glycerol or sorbitol, and a plasticizer. The push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, 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, for example a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration should be in a dosage suitable for such administration.

For buccal administration, the compositions may be formulated in the form of tablets or lozenges in accordance with conventional methods.

For administration by inhalation, the compounds used in the present 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 a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The present disclosure also discloses various pharmaceutical compositions for use in delivery, including intraocular, intranasal, and otic delivery, as are well known in the pharmaceutical arts. Penetrants appropriate to such applications are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in water-soluble form, such as eye drops, or in gellan gum form or hydrogels, ophthalmic ointments, ophthalmic suspensions, such as microparticles, small polymeric particles suspended in a liquid carrier medium, liposoluble 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, which are typically prepared to mimic nasal secretions in many respects to ensure that normal ciliated function is maintained. As is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, lightly buffered to maintain pH between 5.5 and 6.5, and most often and preferably include an antimicrobial preservative and a suitable pharmaceutical stabilizer. Pharmaceutical formulations for in-the-ear delivery include suspensions and ointments for topical application in the ear. Common solvents for such otic formulations include glycerin and water.

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

In addition to the aforementioned formulations, the compounds may also be formulated as depot formulations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, suitable polymers or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins may be used to formulate the compounds, or as sparingly soluble derivatives, such as, for example, a sparingly soluble salt.

For hydrophobic compounds, a suitable pharmaceutical carrier may be a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water miscible organic polymer, and an aqueous phase. The common co-solvent system used was a VPD co-solvent system of 3% w/v benzyl alcohol, 8% w/v non-polar surfactant Polysorbate (POLYSORBATE) 80. TM. And 65% w/v polyethylene glycol 300, with the volume of solution being made up by absolute ethanol. Of course, the proportion of the co-solvent system can be varied considerably without compromising its solubility and toxicity characteristics. In addition, the co-solvent component may be varied, for example, other low toxicity non-polar surfactants may be used in place of polysorbate 80TM, the fragment size of polyethylene glycol may be varied, other biocompatible polymers such as polyvinylpyrrolidone may be substituted for polyethylene glycol, and other sugars or polysaccharides may be substituted for glucose.

Or other delivery systems for hydrophobic drug compounds may be employed. Well-known examples of delivery media or carriers for hydrophobic drugs are liposomes and emulsions. Although generally at the expense of higher toxicity, certain organic solvents, such as dimethyl sulfoxide, may also be employed. In addition, the compounds may be delivered using a slow release system, such as a semipermeable matrix of solid hydrophobic polymer containing the therapeutic agent. Many slow release materials are known and established by those skilled in the art. Depending on its chemical nature, a slow release capsule may release the compound over several weeks to 100 days.

Agents for intracellular administration are administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. Upon formation of liposomes, all molecules present in the aqueous solution are incorporated into the aqueous interior. The contents of the liposome are not only not affected by the external microenvironment, but are efficiently delivered to the cytoplasm due to the fusion of the liposome with the cell membrane. Liposomes can be coated with tissue specific antibodies. Liposomes will be targeted to and selectively taken up by the desired organ. Or small hydrophobic organic molecules may be administered directly intracellularly.

Administration method

The compound or pharmaceutical composition may be administered to the patient by any suitable method. Non-limiting examples of methods of administration include (a) administration by oral route, including administration in the form of a capsule, tablet, granule, spray, syrup, or other such form, (b) administration by non-oral route, such as rectal, vaginal, intra-urethral, intra-ocular, intranasal, or intra-aural, including administration in the form of an aqueous suspension, oily formulation, or the like, or in the form of drops, spray, suppository, ointment, or the like, (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, or the like, including infusion pump delivery, (d) local (locally) such as injection directly in the renal or cardiac area, such as by depot implantation, and local (topically) administration, as appropriate administration by those of skill in the art is by contacting the compounds of the present invention with living tissue.

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 methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other considerations related to the delivery of the compounds to a subject in need thereof.

Pharmaceutical compositions suitable for administration include those which contain an effective amount of the active ingredient to achieve its intended effect. The dosage required for a therapeutically effective amount of the disclosed pharmaceutical compositions depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage may be adjusted to achieve the desired effect, but will depend on the weight, diet, concurrent medication, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prevent, reduce or ameliorate symptoms of a disease, or to extend the life of an individual receiving treatment. The actual ability of those skilled in the art to determine a therapeutically effective amount is well within the scope of the detailed disclosure provided herein.

As will be apparent to those skilled in the art, the dosage and particular mode of administration used for in vivo administration will vary depending upon the age, weight and type of mammal being treated, the particular compound being used, and the particular use for which such compound is being used. The aim of determining an effective dosage level, i.e. the dosage level necessary to determine the desired effect, can be achieved by the person skilled in the art using conventional pharmacological methods. Generally, the human clinical application of the compound is started at lower dosage levels, with the dosage level increasing until the desired effect is achieved. Or using established pharmacological methods, an acceptable in vitro study can be used to establish effective dosages and routes of administration for the compositions identified by the present methods.

In non-human animal studies, the use of potential compounds begins at higher dosage levels, with the dosage decreasing until the desired effect is no longer achieved or the adverse side effects disappear. The dosage range may be wide depending on the intended effect and the therapeutic indication. Generally, the dosage may be from about 10 μg/kg body weight to 500mg/kg body weight, preferably from about 100 μg/kg body weight to 200mg/kg body weight. Or as will be appreciated by those skilled in the art, the dosage may be based on and calculated from the surface area of the patient.

Each physician is able to select the exact formulation, route of administration and dosage of the pharmaceutical composition of the invention, depending on the condition of the patient. Generally, the dosage of the composition administered to the patient may range from about 0.5mg/kg to 1000mg/kg of patient body weight. The dose may be administered alone or in two or more doses over a single day or days, depending on the patient's needs. Where the human dosage of the compound is established for at least some conditions, the present invention will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosage, more preferably dosages ranging from 25% to 250% of the established human dosage. Without a defined human dose, as in the case of the newly discovered pharmaceutical compounds, a suitable human dose can be inferred from ED ₅₀ or ID ₅₀ values, or other suitable values from in vitro or in vivo studies, as quantified by toxicity and efficacy studies in animals.

It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust administration. Conversely, if the clinical response is inadequate (toxicity is excluded), the attending physician will also know to adjust the treatment to a higher level. The size of the dose administered in the treatment of the condition of interest will vary with the severity of the disease state being treated and the route of administration. The severity of the disease state may be assessed, for example, in part by standard prognostic assessment methods. Furthermore, the dose and possibly the frequency of doses will also vary according to the age, weight, and response of the individual patient. Protocols comparable to those discussed above may be used in veterinary medicine.

While the exact dosage may be determined on a drug-by-drug basis, in most cases some generalization can be made with respect to the agent. The daily dosage regimen for adult patients is, for example, an oral dose of 0.1mg to 2000mg of each active ingredient, preferably 1mg to 1000mg of each active ingredient, for example 5 to 500mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01mg to 1000mg, preferably from 0.1mg to 800mg, for example from 1 to 200mg. In the case of administration of pharmaceutically acceptable salts, the dosage may be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions of the invention may be administered by continuous intravenous infusion, preferably at doses of up to 1000mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain instances, it is necessary to administer the disclosed compounds in amounts exceeding or far exceeding the preferred dosage ranges described above in order to effectively and rapidly treat a rapidly developing disease or infection. In certain embodiments, the compound is administered during a continuous treatment period, e.g., one or more weeks, or months or years.

The dosage and dosage interval may be individually adjusted to provide a plasma level of the active moiety sufficient to maintain a modulating effect or Minimum Effective Concentration (MEC). The MEC for each compound was different, but the MEC could be assessed from in vitro data. The required dose to achieve MEC depends on the individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

The use of MEC values also enables the dosing interval to be determined. The composition should be administered using a treatment regimen that maintains plasma levels above MEC for 10-90% of the time, preferably 30-90% of the time, and more preferably 50-90% of the time.

In the case of local administration or selective absorption, the effective local concentration of the drug is independent of plasma concentration.

The amount of composition administered will, of course, depend on the individual to be treated, on the weight of the individual, the severity of the affliction, the mode of administration and the discretion of the prescribing physician.

The potency and toxicity of the presently disclosed compounds can be assessed using known methods. For example, the toxicology of a particular compound or subset of compounds sharing certain chemical moieties can be established by assaying the toxicity of a cell line, such as a mammalian cell line and preferably a human cell line, in vitro. The results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, in humans. Alternatively, toxicity of a particular compound in an animal model such as mouse, rat, rabbit or monkey can be determined using known methods. The potency of a particular compound can be determined using several well-known methods, such as in vitro methods, animal models, or human clinical trials. There are well-known in vitro models for almost every type of disease state, including but not limited to cancer, cardiovascular disease and various immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemicals to treat these disease states. When selecting a model to determine efficacy, the skilled artisan is able to select the appropriate model, dosage and route of administration, as well as treatment regimen, under the direction of the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

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 package may for example comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may carry instructions for administration. The packaging or dispensing device may also carry precautions associated with the container, the precautions being prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which precautions reflect approval of the pharmaceutical form by the agency for human or veterinary administration. Such precautions may be, for example, labels approved by the U.S. food and drug administration for prescription drugs, or approved product specifications. Compositions comprising the compounds of the invention formulated in compatible pharmaceutical carriers may also be prepared in suitable containers and labeled for use in the treatment of the indicated disease state.

Preparation of the Compounds

Although any person skilled in the art will be able to prepare the compounds of the present application according to the general techniques disclosed above, for convenience, more detailed techniques for synthesizing 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 are available from common commercial sources. For example, various reagents used in the examples, including deuterated reagents, are available from Sigma-Aldrich Company Ltd.

¹ HNMR was measured using deuterated dimethyl sulfoxide at a frequency of 500MHz at about 20-30 ℃ unless otherwise specified. Standard NMR abbreviations are used s=singlet, d=doublet, dd=doublet of doublet, t=triplet, q=quartet, p=quintet, m=multiplet, br=broadband.

Example 15 preparation of methoxy-1- (m-toluenesulfonyl) -2- (2, 4, 5-trifluorophenyl) -1H-imidazole (Compound 1)

(1) Synthesis of Compound 1-C

Compound 1-A (440 mg) and compound 1-B (1 g) were mixed, aqueous ammonia (25 mL) was added, and the mixture was heated under reflux for 3 hours. Cooling to room temperature, diluting the reaction solution with ethyl acetate, carrying out suction filtration, concentrating the filtrate, and separating and purifying by column chromatography to obtain the compound 1-C with the yield of 67%.

(2) Synthesis of Compound 1

To compound 1-C (780 mg) and 3-methylbenzenesulfonyl chloride were mixed at 0 ℃, N-Diisopropylethylamine (DIPEA) (6 mL) was added dropwise thereto, stirring was maintained at 0 ℃ for 3h, extraction was performed with ethyl acetate (10 ml×5), the organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂SO₄, filtered, concentrated, and purified by column chromatography to give compound 1 in 43% yield.

Example 25 preparation of ethyl-1- ((3-fluorophenyl) sulfonyl) -2- (2, 4, 5-trifluorophenyl) -1H-imidazole (Compound 3)

According to reference example 1,1-A is replaced by 3-A, 3-methylbenzenesulfonyl chloride is replaced by 3-fluorobenzenesulfonyl chloride, and the compound 3 is prepared with the yield of 30% -40%.

Other synthetic methods of the compounds were as in preparation example 1, with only the replacement of the corresponding starting materials.

Biological example 1

1.1 Cell culture

HT29 human colon cancer cells were obtained from the China academy of sciences typical culture Collection Committee cell Bank (China, shanghai). HT29 cells were cultured in an incubator containing 10% by volume of fetal bovine serum, 50. Mu.g/mL ampicillin, 100. Mu.g/mL streptomycin sulphate McCoy's 5A medium (GIBCO, cat. No. 12800017, containing D-Glucose 4500.0mg/L, naHCO ₃ 2.2.2 g/L added) at 37℃with 5% by volume CO ₂ (air).

1.2 Cell activity assay for 5-HT receptor antagonists

HT29 cells were seeded at a density of 2X 104 cells/well into 384 well biosensor microplates, incubated in an incubator at 37℃with 5% CO2 (air) by volume for 22h, washed 1 time with HBSS buffer prior to detection, added with 30. Mu.L HBSS buffer per well, and incubated on the system for 1h at equilibrium. After equilibration, a baseline of 2min was established on the system and then 10mL of scopolamine, scopolamine (14 concentration points for each compound, 10 μm maximum working concentration, 2-fold stepwise dilution, 5 μm,2.5 μm,1.25 μm etc.) was added to 384-well biosensor microplates inoculated with HT29 cells, respectively, to determine the antagonistic activity of the compounds on muscarinic M receptors.

Absorbance readings for each well were collected by SoftMaxPro software and imported into a Microsoft Excel spreadsheet for further calculations. Outliers were detected by Grubbs test built in GRAPHPAD PRISM. For each well, percent Virus Reduction (PVR) calculation was calculated using the formula, and the half inhibition concentration (EC ₅₀) was calculated by calculating the concentration-response curve for each test sample by 4-parameter nonlinear regression curve fitting.

The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. Any person skilled in the art will make any equivalent substitution or modification to the technical solution and technical content disclosed in the patent without departing from the scope of the technical solution of the patent, and all the technical solution of the patent still falls within the protection scope of the patent.

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein, R ₁ is selected from any one of C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₂-C₆ alkenyl, C ₁-C₆ haloalkyl, C ₁-C₆ deuterated alkyl and C ₁-C₆ alkyl hydroxy;

R ₂ is selected from any one of hydrogen, deuterium, halogen and cyano;

n=2, 3 or 4;

R ₃ is selected from any one of hydrogen, deuterium, halogen, cyano, hydroxy, amino, C ₁-C₆ alkyl and C ₂-C₆ alkenyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from any one of C ₁-C₃ alkyl, C ₁-C₃ alkoxy, -ch=ch ₂、-CH₂CF₃、CD₃, and C ₁-C₃ alkyl hydroxy.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from halogen.

4. A compound or pharmaceutically acceptable salt as claimed in claim 3, wherein R ₂ is selected from fluorine or bromine, n = 2 or 3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₃ is selected from any one of hydrogen, methyl, fluoro, bromo, -NH ₂, hydroxy, and-ch=ch ₂.

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

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 a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and treatment of 5-HT receptor mediated diseases.

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

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