Novel pyrrolidinium compounds with antagonistic activity against muscarinic receptors and their applications

Abstract

The present invention relates to novel pyrrolidinium compounds, stereoisomers thereof, hydrates thereof, or solvates thereof, which exhibit excellent binding ability and antagonistic activity to muscarinic receptors, particularly muscarinic M3 receptors. [Solution] The compounds of the present invention are useful in treating muscarinic acetylcholine receptor-mediated diseases such as hyperhidrosis, excessive salivation, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, urinary incontinence, overactive bladder syndrome, gastroesophageal reflux disease, and irritable bowel syndrome.

Description

Technical Field

[0001] The present invention relates to a novel pyrrolidinium compound having an antagonistic activity against a muscarinic receptor, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, a pharmaceutical composition containing the same as an active ingredient, and a pharmaceutical use thereof.

Background Art

[0002] Muscarinic acetylcholine receptors (mAChRs) belong to a superfamily of G protein-coupled receptors having seven transmembrane domains. There are five subtypes of mAChRs called M1 to M5, each of which exhibits unique pharmacological properties. For example, stimulation of the M3 receptor in the airway causes contraction of airway smooth muscle, leading to bronchoconstriction, and stimulation of the M3 receptor in the salivary gland and sweat gland increases body fluid and mucosal secretion, increasing saliva and sweat secretion.

[0003] Muscarinic receptor antagonists act by inhibiting the binding of acetylcholine to muscarinic cholinergic receptors at various action sites in the body such as smooth muscle, myocardium, peripheral ganglia, and central nervous system. Therefore, muscarinic receptor antagonists are known to be useful for the treatment of various diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, rhinitis, hypersalivation, hyperhidrosis, urinary incontinence, overactive bladder syndrome, gastroesophageal reflux disease, and irritable bowel syndrome.

[0004] Therefore, the present inventors have completed the present invention by preparing a novel pyrrolidinium compound showing excellent antagonistic activity against muscarinic receptors, particularly muscarinic M3 receptors.

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a solvate thereof.

[0006] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating muscarinic acetylcholine receptor-mediated diseases, comprising a compound represented by Formula 1, its stereoisomer, its hydrate, or its solvate, and a pharmaceutically acceptable carrier.

[0007] Another object of the present invention is to provide a method for preventing or treating muscarinic acetylcholine receptor-mediated diseases, comprising the step of administering or topically applying a compound represented by Formula 1, its stereoisomer, its hydrate, or its solvate to a target. [Means for solving the problem]

[0008] Each description and embodiment disclosed herein may also apply to each of the other descriptions and embodiments. That is, all combinations of the various elements disclosed herein fall within the scope of this application. Furthermore, the scope of this application should not be construed as being limited by the specific descriptions set forth below.

[0009] The present invention relates to the following formula 1 [Formula 1] A compound represented by TIFF2026511228000002.tif41170, its stereoisomer, its hydrate, or its solvate, In formula 1, R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, dialkylamino, and aminocarbonyl. R 3 is hydrogen or a C1-C6 alkyl group. R 4 It either does not exist, or is A, -OC(O)-A, -OA, or -C(O)-A. A is a 5- to 6-membered heteroaryl or 5- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, or S, wherein the 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl may be optionally substituted with oxo, halogen, hydroxy, cyano, amino, C1-C6 alkyl, or C1-C6 alkoxy, n and m are each independently an integer from 0 to 3, k is an integer from 1 to 3, p is an integer from 1 to 5, and X - is a monovalent anion, and provides a compound, its stereoisomer, its hydrate, or its solvate.

[0010] In Formula 1 of the present invention, R 1 and R 2 may each independently be selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, dialkylamino, and aminocarbonyl. In some embodiments, R 1 and R 2 may each independently be hydrogen, halogen, hydroxy, cyano, or C1-C3 alkoxy. In one embodiment, R 1 and R 2 may each independently be hydrogen or halogen. In this case, the halogen may be F, Cl, Br, or I. For example, the halogen may be F or Cl. In one embodiment, R 1 is halogen (e.g., F, Cl, Br, or I), and R 2 may be hydrogen. In one embodiment, R 1 may be hydrogen, and R 2 may be halogen (e.g., F, Cl, Br, or I). In one embodiment, R 1 and R 2 may both be hydrogen.

[0011] In the above formula 1, n and m are each independently 0, 1, 2, or 3. In some embodiments, n and m may each independently be 0, 1, or 2. When n and m are each independently 2 or 3, multiple R 1 and R 2 These may be identical to each other, or they may be different.

[0012] In formula 1 of the present invention, R 3 is hydrogen or a C1-C6 alkyl group. In one embodiment, R 3 This may be a C1-C6 alkyl group. For example, R 3 This may be a C1-C3 alkyl group. For example, R 3 This may be methyl, ethyl, propyl, or isopropyl.

[0013] In Formula 1 of the present invention, p is an integer from 1 to 5. In some embodiments, p may be 1, 2, or 3.

[0014] In formula 1 of the present invention, R 4 A is either absent, -A, -OC(O)-A, -OA, or -C(O)-A. In this case, A is a 5-6 member heteroaryl or 5-6 member heterocycloalkyl. The 5-6 member heteroaryl or 5-6 member heterocycloalkyl may contain 1 to 3 heteroatoms selected from N, O, or S. For example, a 5-6 member heteroaryl may include, but is not limited to, pyridine, pyrimidine, pyrrolyl, pyrazolyl, furanyl, thiophenyl, etc. For example, a 5-6 member heterocycloalkyl may include, but is not limited to, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolyl, 1,3-dioxolanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, etc. A may be optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, hydroxy, cyano, amino, C1-C6 alkyl, and C1-C6 alkoxy.

[0015] In some embodiments, R 4 It may not be present, and may be -A or -OC(O)-A. In this case, A is pyridinyl or 2-oxo-1,3-dioxol-4-yl( TIFF2026511228000003.tif15170) or 1,3-Dioxol-4-yl TIFF2026511228000004.tif11170) may also be used. The A may be optionally substituted with a halogen, hydroxyl, cyano, amino, C1-C3 alkyl, or C1-C3 alkoxy. In one embodiment, the A may be optionally substituted with a C1-C3 alkyl such as methyl or ethyl. In one embodiment, R 4 It does not have to exist. In this case, in the formula, TIFF2026511228000005.tif15170 may have a methyl ester, ethyl ester, or propyl ester structure.

[0016] In formula 1 of the present invention, X - X is a monovalent anion. - This is pyrrolidinium N + It is not particularly limited as long as it can form a salt with X - This may be a chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, or p-toluenesulfonate. For example, X - This may be a chloride, bromide, 4-toluenesulfonate, or methanesulfonate. Preferably, X - It may also be a bromide.

[0017] In one embodiment, the compound of the present invention is You may also select from TIFF2026511228000006.tif152170.

[0018] definition All technical and scientific terms used herein have meanings generally understood by those skilled in the art, and unless otherwise specified, conventional measurement methods, manufacturing methods, and conventional components or substances are used in the context of conventional arts such as pharmacology, medicinal chemistry, mass spectrometry, NMR, HPLC, and biochemistry.

[0019] The individual features and components of each embodiment described and illustrated herein may be combined with any other features and components of any other embodiment without departing from the scope or spirit of this disclosure.

[0020] Unless otherwise specified, in this specification and in the claims, “or” and “and” mean “and / or.” The terms “contains” and “contains” are open-ended, meaning that a compound, composition, or method may contain additional features or components in addition to the specific features or components listed.

[0021] In this specification, a numerical range indicated by the term "~" refers to a range that includes the numbers before and after the term "~" as the lower and upper limits, respectively.

[0022] As used herein, the terms “optional” or “optionally” mean that the event or situation described therein may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not. For example, the term “optionally substituted” means both substitution by a particular substituent and non-substitution.

[0023] compound As used herein, unless otherwise specified, the term "alkyl" refers to saturated linear and saturated branched carbon chains having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, whether used alone or as part of a substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0024] The term "alkoxy" refers to an -O-alkyl group. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, and tert-butoxy.

[0025] The term "heteroatom" refers to nitrogen, oxygen, or sulfur, such as N(O)(N + -O - It includes any oxidation form of nitrogen, such as ), any oxidation form of sulfur, such as S(O) and S(O)2, and any basic quaternization form of nitrogen.

[0026] The term "heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms, with the remaining ring atoms being carbon. A heteroaryl group may contain, for example, 1 to 3 heteroatoms, 1 or 2 heteroatoms. A heteroaryl group may contain 5 to 10 ring elements, 5 to 7 ring elements, or 5 or 6 ring elements. Examples of "heteroaryls" include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl.

[0027] The terms "heterocycloalkyl," "heterocyclic," or "heterocyclic" refer to saturated or partially unsaturated cyclic groups containing one or more heteroatoms, with the remaining ring atoms being carbon atoms. Heterocycloalkyl groups may contain, for example, 1 to 3, 1, or 2 heteroatoms. Heterocycloalkyl groups may contain 5 to 10 ring elements, 5 to 7 ring elements, or 5 or 6 ring elements. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolyl, 1,3-dioxolanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-pyrrolidone-1-yl, and morpholinyl.

[0028] The term "oxo" refers to the (=O) group.

[0029] As used herein, the term "halogen" refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine, and may be used interchangeably with the term "halo," which refers to a monovalent functional group composed of halogens.

[0030] As used herein, the term "hydroxy" refers to the -OH functional group (hydroxyl group).

[0031] As used herein, the term "cyano" is -CN and refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

[0032] As used herein, the term "amino" refers to -NH2.

[0033] As used herein, the term "alkylamino" refers to a group in which one of the two hydrogen atoms in the amino group is replaced by an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and propylamino.

[0034] As used herein, the term “dialkylamino” refers to -N(alkyl)2. In this case, the two alkyl groups may be the same or different. Examples of dialkylamino substituents include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, and dipropylamino.

[0035] As used herein, the term "nitro" refers to -NO2.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. The halogens may be the same (e.g., CHF2, -CF3) or different (e.g., CF2Cl). Where specified, a haloalkyl group may optionally be substituted with one or more substituents other than halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0037] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, where alkoxy is as defined above. Non-limiting examples of haloalkoxy groups may include fluoromethoxy, dichloroethoxy, trifluoromethoxy, trichloromethoxy, and the like.

[0038] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more -OH groups, where alkyl is as defined above.

[0039] As used herein, the term "aminocarbonyl" refers to an amino acid bonded to a carbonyl group via a nitrogen atom.

[0040] In this specification, In JPEG2026511228000007.jpg6170, the asterisk (*) or hyphen (-) is used to indicate the position of a substituent to which it is attached to the rest of the compound. For example, if a hyphen is shown at the end of a substituent, it means that the end is attached to the rest of the compound. Furthermore, if two or more substituents are linked by a hyphen, it means that the substituent immediately preceding the hyphen is attached to a substitutable atom of the substituent immediately following the hyphen.

[0041] As used herein, the term “solvate” may refer to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bonded by non-covalent intermolecular forces. The preferred solvent for this purpose may be volatile, non-toxic, and / or suitable for administration to humans. The solvent may be water, in which case the “solvate” is referred to as the “hydrate.”

[0042] As used herein, the term “stereoisomer” may refer to a compound or salt thereof of the present invention having the same chemical or molecular formula but being optically or sterically different, and may specifically be a diastereomer, enantiomer, or geometric isomer.

[0043] In some embodiments, the compounds of the present invention contain one or more chiral centers and may be in the form of a racemate, a single enantiomer, a mixture of enantiomers, a single diastereomer, a mixture of diastereomers, and so on. In one embodiment, due to the properties of the chiral center or limited rotation, the compounds of the present invention may exist in the form of an enantiomer or a diastereomer.

[0044] If the compounds of the present invention contain two or more chiral centers, multiple diastereomers and enantiomers of the chemical structures disclosed herein may exist. Pure isomers, separated isomers, partially pure isomers, or racemic mixtures are all intended to be within the scope of the present invention.

[0045] The purification of isomers and the separation of isomeric mixtures can be achieved by standard techniques known in the art. For example, diastereomer mixtures can be separated into their respective diastereomers by chromatography or crystallization, and racemates can be separated into their respective enantiomers by chromatography or chiral phase separation.

[0046] The compound represented by Formula 1 according to the present invention is a quaternary ammonium salt and can be converted to various salt forms by ion exchange chromatography. The compound can be obtained in the form of a hydrate or solvate. The compound represented by Formula 1 may be recovered from the reaction mixture and purified by known methods. If the compound represented by Formula 1 contains a chiral carbon, the compound may be used as a diastereomer mixture or as a single enantiomer or diastereomer.

[0047] Furthermore, the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, for example, the salts may be derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like.

[0048] A pharmaceutically acceptable salt of the compound may be prepared by dissolving the compound of formula 1 in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing it. Subsequently, the addition salt may be prepared by evaporating the solvent or excess acid from the mixture and then drying it, or by suction filtration of the precipitated salt.

[0049] General compound preparation methods The compounds according to the present invention can be readily prepared from commercially available starting materials, compounds known in the literature, or intermediates readily prepared therefrom by standard synthetic methods and procedures in the relevant field.

[0050] The methods described herein can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., ultraviolet-visible light), mass spectrometry, or chromatography such as high-performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin-layer chromatography (TLC).

[0051] The following general reaction scheme illustrates a typical method for preparing compounds represented by Formula 1. Those skilled in the art can easily prepare compounds represented by Formula 1 by appropriately selecting suitable starting materials, reaction temperature, reaction conditions, catalyst, solvent, processing method, etc., based on the production methods specifically disclosed in the examples herein. Hereinafter, unless otherwise specified, the designation of each substituent in Formula 1 in the reaction scheme is the same as the designation of the substituent at the corresponding position in Formula 1.

[0052] In one embodiment, the compound represented by formula 1 is given by the following formula A1 [Formula A1] Intermediate A1 represented by TIFF2026511228000008.tif36170 is given by the following formula B1 [Formula B1] BrCH2COO-(CH2) p -R 4 It can be prepared by reacting it with a bromoacetate compound represented by .

[0053] The bromoacetate compound represented by formula B1 is the R of the final target product. 4Depending on the requirements, appropriate selections may be made, for example, ethyl 2-bromoacetate, methyl 2-bromoacetate, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-bromoacetate, etc.

[0054] The bromoacetate compound represented by formula B1 can be replaced with other halogenated acetate compounds as needed. In this case, X - Halides in which the halogen anion is other than a bromide (for example, I - Cl - ) can be obtained.

[0055] In one embodiment, the compound represented by formula 1 is given by the following formula A2 [Formula A2] Intermediate A2 represented by TIFF2026511228000009.tif36170 is expressed in the following formula B2 [Formula B2] HO-(CH2) p -OC(O)-A It can be prepared by reacting it with a hydroxyalkyl ester compound represented by .

[0056] The hydroxyalkyl ester compound represented by formula B2 is the final target product R 4 It can be appropriately selected depending on the circumstances, and for example, 3-hydroxypropylnicotinate may be used.

[0057] Pharmaceutical uses, pharmaceutical compositions, and methods of administration In another embodiment, a pharmaceutical composition for the prevention or treatment of muscarinic acetylcholine receptor-mediated diseases is provided, comprising a compound represented by Formula 1, its stereoisomer, its hydrate, or its solvate. The compound represented by Formula 1, its stereoisomer, its hydrate, and its solvate are as described above.

[0058] As used herein, the terms “prevention” or “prevention” mean preventing disease, for example, preventing disease, condition or disorder in an object that may have a predisposition to disease, condition or disorder but has not yet experienced or shown any symptoms or signs of disease.

[0059] As used herein, the terms “to treat” or “to treat” mean to suppress a disease, for example, to inhibit a disease, condition or disorder in an object experiencing or exhibiting the pathology or signs of a disease, condition or disorder, i.e., to prevent further development of the pathology and / or signs; or to improve a disease, for example, to improve a disease, condition or disorder in an object experiencing or exhibiting the pathology or signs of a disease, condition or disorder, i.e., to reverse the pathology and / or signs, for example, to reduce the severity of the disease.

[0060] Muscarinic acetylcholine receptor-mediated diseases refer to diseases that can be prevented or treated by inhibiting the binding of acetylcholine to muscarinic receptors, particularly muscarinic M3 receptors. The compounds of the present invention have excellent antagonistic activity against muscarinic acetylcholine receptors, particularly muscarinic M3 receptors. Specifically, when the antagonistic activity against human muscarinic M3 receptors was measured according to the method described in Experimental Example 1 herein, the compounds of the present invention showed excellent IC at the nM level. 50 It was confirmed that it has a value.

[0061] Therefore, the compounds of the present invention have excellent antagonistic activity against muscarinic acetylcholine receptors, particularly muscarinic M3 receptors, and are useful for the prevention or treatment of various muscarinic acetylcholine receptor-mediated diseases. In some embodiments, the compounds of the present invention can be effectively used for the prevention or treatment of hyperhidrosis, excessive salivation, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, urinary incontinence, overactive bladder syndrome, gastroesophageal reflux disease, or irritable bowel syndrome.

[0062] In one embodiment, the pharmaceutical composition may contain conventionally pharmaceutically acceptable carriers, excipients, or additives. The pharmaceutical composition may be formulated according to conventional methods and may be prepared as various oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, and microemulsions, or as parenteral formulations such as intramuscular, intravenous, or subcutaneous formulations, or as formulations for topical application to the skin. The pharmaceutical composition may be a single composition or separate compositions. The pharmaceutical composition may contain, in one embodiment, a compound, stereoisomer, hydrate, or solvate as the active ingredient of the pharmaceutical composition.

[0063] When the pharmaceutical composition is prepared in the form of an oral formulation, examples of additives or carriers used may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additives or carriers may include water, physiological saline, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc.

[0064] The dosage of the pharmaceutical composition is an effective amount for treating or preventing the disease of the subject or patient, and may be administered orally or parenterally as desired. When administered orally, the dose is 0.01 to 1000 mg per kg of body weight per day, more specifically 0.1 to 300 mg, based on the active ingredient. When administered parenterally, the dose is 0.01 to 100 mg per kg of body weight per day, more specifically 0.1 to 50 mg, based on the active ingredient, and may be administered in one to several divided doses. It should be understood that the dose to be administered to a specific subject or patient should be determined considering several relevant factors such as the patient's weight, age, sex, and health status, diet, administration time, method of administration, and disease severity, and may be increased or decreased as appropriate by a professional. The above dosages are not intended to limit the scope of the present invention in any way. Physicians or veterinarians skilled in the art can easily determine and prescribe the necessary effective amount of the pharmaceutical composition. For example, the dose of the compound of the present invention used in a pharmaceutical composition may be started at a level lower than necessary to achieve the desired therapeutic effect, and may be gradually increased until the desired effect is achieved, as determined by a physician or veterinarian.

[0065] In one embodiment, the pharmaceutical composition includes, within its scope, a pharmaceutical composition comprising, as an active ingredient, at least one of the compounds according to one embodiment, in a therapeutically effective amount, alone or in combination with a pharmaceutically acceptable carrier. The terms “therapeutically effective amount” or “effective amount” mean an amount sufficient to produce a beneficial or desired clinical outcome, for example, an amount sufficient to reduce, improve, stabilize, reverse, inhibit or delay the progression of a disease.

[0066] When the composition of the present invention is used for the prevention or treatment of hyperhidrosis, the composition of the present invention may be formulated into formulations for topical application to the skin, such as solids, semi-solids, powders, gels, ointments, creams, lotions, foams, solutions, suspensions, aerosols, patches, and emulsions. In one embodiment, the formulation for topical application of the present invention may be a gel, cream, emulsion, lotion, or spray.

[0067] In one embodiment, gels, ointments, and creams may be formulated using, for example, a suitable thickener and / or gelling agent and / or an aqueous or oily base. For example, they may contain water and / or oils such as liquid paraffin, or vegetable oils such as peanut oil or castor oil, or glycol solvents such as propylene glycol or 1,3-butanediol. For example, thickeners may include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin fat, hydrogenated lanolin and beeswax and / or glyceryl monostearate and / or nonionic emulsifiers. In one embodiment, lotions may be formulated using an aqueous or oily base and may contain one or more of emulsifiers, dispersants, suspending agents, thickeners, solvents, colorants, and flavoring agents. Powders can be formed using any suitable powder base such as talc, lactose, or starch. The spray composition may be formulated as an aerosol using a suitable propellant, such as dichlorodifluoromethane or trichlorofluoromethane.

[0068] The proportion of the active ingredient in the topical formulation according to the present invention varies depending on the compound used, the type of formulation, and the specific conditions under which the composition is administered. For example, the topical formulation may contain about 0.1% to about 50%, about 1% to about 30%, or about 5% to about 20% of the compound of the present invention.

[0069] When used to treat hyperhidrosis, the topical formulation may be applied topically, as needed, to the area of ​​skin where sweating needs to be reduced, such as the palms of the hands, soles of the feet, groin, armpits, or face. The topical formulation may be applied to the subject as needed, for example, more than once a week, three to four times a week, once a day, twice a day, or three times a day.

[0070] In another embodiment, a method is provided for preventing or treating a muscarinic acetylcholine receptor-mediated disease, comprising the step of administering or topically applying a compound represented by Formula 1, its stereoisomer, its hydrate, or its solvate to a target.

[0071] Any terms or elements mentioned in this description of the method that are the same as those mentioned above are as described above.

[0072] Administration may be oral or parenteral. When administered orally, the dose should be 0.01 to 1000 mg per kg of body weight per day, more specifically 0.1 to 300 mg, based on the active ingredient. When administered parenterally, the dose should be 0.01 to 100 mg per kg of body weight per day, more specifically 0.1 to 50 mg, based on the active ingredient, and may be administered in one to several divided doses.

[0073] The dosage administered to a specific subject or patient should be determined by considering several relevant factors, including the patient's weight, age, sex, and health status, diet, timing of administration, method of administration, and severity of the disease, and may be increased or decreased as appropriate by a specialist.

[0074] In some embodiments, when the method of the present invention is used to treat hyperhidrosis in a subject, the formulation of the present invention may be applied topically to a site of skin in the subject where sweating needs to be reduced. In one embodiment, the site of skin in the subject may include the palms of the hands, soles of the feet, groin, armpits, or face. The compound of the present invention may be applied to the subject as needed, for example, more than once a week, three to four times a week, once a day, twice a day, or three times a day. Depending on the method of the present invention, sweating can be reduced by about 10% to about 99%, about 30% to about 80%, or at least 50%.

[0075] As used herein, the term “subject” refers to a subject requiring treatment for a disease, and more specifically, to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle.

[0076] In another embodiment, pharmaceutical uses of the compound represented by Formula 1, its stereoisomers, its hydrates, or its solvates for the prevention or treatment of muscarinic acetylcholine receptor-mediated diseases are provided, or uses of the compound represented by Formula 1, its stereoisomers, its hydrates, or its solvates for the manufacture of pharmaceuticals for the prevention or treatment of muscarinic acetylcholine receptor-mediated diseases are provided. Terms or elements mentioned in the description of the uses that are the same as those mentioned above are as described above. [Effects of the Invention]

[0077] The compound represented by Formula 1, its stereoisomers, its hydrates, or its solvates exhibit excellent antagonistic activity against muscarinic M3 receptors and are useful for the prevention or treatment of various diseases, particularly hyperhidrosis, hypersalivation, chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, glaucoma, and cardiac arrhythmias. [Brief explanation of the drawing]

[0078] [Figure 1] Figure 1 is a graph showing the results obtained by measuring the number of sweat spots per hind limb sole in the normal group (vehicle), the hyperhidrosis induction group, the positive control group administered 20% sofpyronium, and the experimental groups administered 20% compound 1 and 20% compound 3, respectively. ##p<0.01 vs normal group;**p<0.01 vs induction group (one-way ANOVA, LSD post-hoc test) [Modes for carrying out the invention]

[0079] Detailed description for carrying out the invention The present invention will be described in detail below with reference to examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

[0080] Preparation example Preparation Example 1-1: Synthesis of (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate TIFF2026511228000010.tif36170

[0081] 3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid (0.80 g, 3.19 mmol) and (R)-(1-methylpyrrolidine-3-yl)methanol (0.40 g, 3.51 mmol) were dissolved in toluene (8 mL). Triethylamine (0.97 g, 9.57 mmol) and diphenyl phosphoryl azide (1.32 g, 4.79 mmol) were added at room temperature, and the mixture was stirred under a nitrogen atmosphere at an external temperature of 120 °C for 12 hours. After the reaction was complete, the temperature of the reactants was cooled to room temperature, and then 1N hydrochloric acid solution (30 mL) was added. This mixture was extracted with ethyl acetate and washed with sodium bicarbonate. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (0.50 g, 43%). MS:m / z[MH] - =362.8 1 HNMR (400MHz, CDCl3): δ7.89(d, J=7.6Hz, 1H), 7.44-7.39(m, 1H), 7.38-7.33(m, 1H), 7.25-7.12(m, 4H), 6.97(t, J=6. 8Hz, 1H), 4.11-3.97(m, 2H), 2.92-2.85(m, 1H), 2.83-2.58(m, 4H), 2.50(s, 3H), 2.10-2.03(m, 1H), 1.71-1.63(m, 1H).

[0082] Preparation Example 1-2: Synthesis of (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (alternative method) TIFF2026511228000011.tif36170

[0083] Step 1: Synthesis of 3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-amine TIFF2026511228000012.tif29170

[0084] (3-chloro-4-fluoro)phenylboronic acid (5.0 g, 28.7 mmol), sodium carbonate (6.6 g, 63.8 mmol), and tetrakistriphenylphosphine palladium (1.8 g, 1.56 mmol) were dissolved in a mixed solvent of toluene (40 mL) and water (20 mL) in a reactor. Then, 2-bromo-4-fluoroaniline (3.8 g, 22.1 mmol) was added, and the mixture was stirred at an external temperature of 95 °C for 18 hours. After the reaction was complete, saturated ammonium solution (50 mL) and dichloromethane (50 mL) were added and stirred, and then the aqueous layer and organic layer were separated. The aqueous layer was extracted with dichloromethane (2 × 50 mL), and then the organic layer was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (2.5 g, 51%).

[0085] Step 2: Synthesis of (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0086] Triphosgene (1.2 g, 4.0 mmol) was dissolved in dichloromethane (30 mL), and then 3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-amine (2.5 g, 11.3 mmol) and triethylamine (3.4 g, 33.9 mmol) were added at 0°C. After reacting at 0°C for 1 hour, (R)-(1-methylpyrrolidine-3-yl)methanol (1.2 g, 10.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with water and dichloromethane, then dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (1.2 g, 31%). MS:m / z[M+H] + =363.2

[0087] Preparation Example 2: Synthesis of (S)-(1-methylpyrrolidine-2-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate TIFF2026511228000013.tif33170

[0088] The title compound (0.50 g, 43%) was obtained by reacting 3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid with (S)-(1-methylpyrrolidine-2-yl)methanol using the same method as in Preparation Example 1-1. MS:m / z[MH] - =362.8 1 H NMR (400MHz, DMSO-d6): δ8.06(d, J=7.6Hz, 1H), 7.47-7.36(m, 2H), 7.30-7.22(m, 2H), 7.21-7.11(m, 2H), 6.56(s, 1H), 4.27-4.08(m, 2H), 3.13-3.07(m, 1H), 2.56-2.46(m, 1H), 2.42(s, 3H), 2.32-2.22(m, 1H), 1.99-1.59(m, 4H).

[0089] Preparation Example 3: Synthesis of 2-(1-methylpyrrolidine-2-yl)ethyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate TIFF2026511228000014.tif32170

[0090] The title compound (0.67 g, 45%) was obtained by reacting 3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid with 2-(1-methylpyrrolidine-2-yl)ethane-1-ol using the same method as in Preparation Example 1-1. MS:m / z[MH] - =376.8 1H NMR (400MHz, CDCl3): δ7.84(d, J=7.6Hz, 1H), 7.58-7.38(m, 1H), 7.32-7.28(m, 1H), 7.24-7.19(m 1H), 7.14-7.03(m, 1H), 6.95(t, J=6.4Hz, 2H), 6.88(s, 1H), 4.17-4.00(m, 2H) , 3.55-3.51(m, 1H), 2.79-2.49(m, 5H), 2.16-2.05(m, 2H), 1.95-1.54(m, 4H).

[0091] Preparation Example 4: Synthesis of 2-(1-methylpyrrolidine-2-yl)ethyl[1,1'-biphenyl]-2-ylcarbamate TIFF2026511228000015.tif33170

[0092] 2-Isocyanato-1,1'-biphenyl (0.50 g, 2.96 mmol) was dissolved in tetrahydrofuran (10 mL), and then 2-(1-methylpyrrolidine-2-yl)ethanol (0.38 g, 2.96 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and then purified by column chromatography to obtain the title compound (0.70 g, 72%). MS:m / z[M+H] + =325.3

[0093] Preparation Example 5: Synthesis of (S)-(1-methylpyrrolidine-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate TIFF2026511228000016.tif30170

[0094] Using 2-isocyanato-1,1'-biphenyl as the starting material and (S)-(1-methylpyrrolidine-2-yl)methanol as the reaction product, the title compound (0.40 g, 84%) was obtained by the same method as in Preparation Example 4. MS:m / z[M+H] + =311.1

[0095] Preparation Example 6: Synthesis of (R)-(1-methylpyrrolidine-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate TIFF2026511228000017.tif30170

[0096] Using 2-isocyanato-1,1'-biphenyl as the starting material and (R)-(1-methylpyrrolidine-3-yl)methanol as the reaction product, the title compound (0.45 g, 94%) was obtained by the same method as in Preparation Example 4. MS:m / z[M+H] + =311.0

[0097] Preparation Example 7: Synthesis of 2-(1-methylpyrrolidine-2-yl)ethyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0098] Step 1: Synthesis of 5-fluoro-[1,1'-biphenyl]-2-amine TIFF2026511228000018.tif32170

[0099] Phenylboronic acid (3.9 g, 31.9 mmol), potassium carbonate (8.8 g, 63.8 mmol), and tetrakistriphenylphosphine palladium (1.8 g, 1.56 mmol) were dissolved in a mixed solvent of toluene (40 mL), water (20 mL), and ethanol (10 mL) in a reactor. Then, 2-bromo-4-fluoroaniline (3.0 g, 15.9 mmol) was added, and the mixture was stirred at an external temperature of 95 °C for 16 hours. After the reaction was complete, saturated ammonium solution (50 mL) and dichloromethane (50 mL) were added and stirred, and then the aqueous layer and organic layer were separated. The aqueous layer was extracted with dichloromethane (2 × 50 mL), and then the organic layer was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (2.9 g, 97%).

[0100] Step 2: Synthesis of 2-(1-methylpyrrolidine-2-yl)ethyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate TIFF2026511228000019.tif29170

[0101] The title compound (2.15 g, 50%) was obtained by reacting 5-fluoro-[1,1'-biphenyl]-2-amine with 2-(1-methylpyrrolidine-2-yl)ethanol using the same method as in step 2 of Preparation Example 1-2. MS:m / z[M+H] + =343.2

[0102] Preparation Example 8: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-bromoacetate TIFF2026511228000020.tif25170

[0103] 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (1.0 g, 7.7 mmol) was dissolved in dichloromethane (10 mL) in a reactor, and then 2-bromoacetyl bromide (1.5 g, 7.7 mmol) and pyridine (1.8 g, 23.1 mmol) were added dropwise at 0°C. The reaction mixture was stirred at room temperature for 18 hours, and then extracted with saturated ammonium solution and dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (1.0 g, 53%).

[0104] Preparation Example 9: Synthesis of (3R)-1-(carboxymethyl)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl-carbamoyl)oxy)methyl)-1-methylpyrrolidine-1-ium bromide TIFF2026511228000021.tif35170

[0105] (3R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl-carbamoyl)oxy)methyl)-1-(2-ethoxy-2-oxomethyl)-1-methylpyrrolidine-1-ium bromide (0.30 g, 0.69 mmol) was dissolved in methanol (10 mL) in a reactor, and then sodium hydroxide solution (0.69 mL, 2N) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC using acetonitrile and water containing 0.1% hydrogen bromide to obtain the title compound (0.20 g, 69%). [Examples]

[0106] Example 1: (3R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (compound 1) TIFF2026511228000022.tif33170

[0107] (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.50 g, 1.38 mmol) was dissolved in acetonitrile (10 mL), and then ethyl 2-bromoacetate (0.46 g, 2.76 mmol) was added dropwise. The mixture was stirred under a nitrogen atmosphere at 25°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain compound 1 (0.38 g, 52%). MS:m / z[M-Br] - =449.2 1H NMR (400MHz, DMSO-d6): δ9.00(d, J=5.6Hz, 1H), 7.57(d, J=6.4Hz, 1H), 7.52-7.46(m, 1H), 7.41-7.33(m, 3H), 7.31-6.95(m, 2H), 4.56(d, J=21.2H) z, 2H), 4.29-4.18(m, 2H), 4.14-3.42(m, 6H), 3.23-3.19(m, 3H), 2.88-2 .81(m, 1H), 2.28-2.21(m, 1H), 1.90-1.75(m, 1H), 1.25(t, J=6.8Hz, 3H).

[0108] Example 2: 2-(2-(([1,1'-biphenyl]-2-ylcarbamoyl)oxy)ethyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (Compound 2) TIFF2026511228000023.tif29170

[0109] Compound 2 (0.33 g, 65%) was obtained using 2-(1-methylpyrrolidine-2-yl)ethyl[1,1'-biphenyl]-2-ylcarbamate (0.40 g, 1.23 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =411.3 1 H NMR (400MHz, DMSO-d6): δ8.70(s, 1H), 7.50-7.27(m, 9H), 4.67-4.27(m, 1H), 4.26-4.18(m, 3H), 4.11-3.83(m, 3H), 3.77 -3.46(m, 2H), 3.10(d, J=112.4Hz, 3H), 2.32-2.13(m, 2H), 2.08-1.99(m, 2H), 1.92-1.69(m, 2H), 1.25(t, J=7.2Hz, 3H).

[0110] Example 3: (2S)-2-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (compound 3) TIFF2026511228000024.tif39170

[0111] Compound 3 (0.40 g, 69%) was obtained using (S)-(1-methylpyrrolidine-2-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.40 g, 3.51 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =448.0 1 H NMR (400MHz, DMSO-d6): δ7.63-7.57(m, 1H), 7.50-7.29(m, 6H), 4.48-4.31(m, 3H), 4.26-4.09(m, 3H), 3.9 5-3.65(m, 2H), 3.43-3.41(m, 2H), 3.09(s, 2H), 2.30-1.99(m, 3H), 1.95-1.82(m, 1H), 1.27-1.22(m, 3H).

[0112] Example 4: 1-(2-ethoxy-2-oxoethyl)-2-(2-(((5-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)ethyl)-1-methylpyrrolidine-1-ium bromide (compound 4) TIFF2026511228000025.tif28170

[0113] Compound 4 (0.53 g, 70%) was obtained using 2-(1-methylpyrrolidine-2-yl)ethyl (5-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.50 g, 1.46 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =429.2 1H NMR (400MHz, CDCl3): δ7.84(dd, J=15.6, 10.4Hz, 1H), 7.55-7.30(m, 5H), 7.19-6.79(m, 3H), 5.40-4.80(m, 1H), 4.68(dd, J=2 0.0, 17.2Hz, 1H), 4.43(m, 1H), 4.33-4.05(m, 6H), 3.60(s, 2H), 3.13(s, 1H), 2.60-1.78(m, 6H), 1.29(td, J=7.2, 1.6Hz, 3H).

[0114] Example 5: (2S)-2-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (Compound 5) TIFF2026511228000026.tif40170

[0115] Compound 5 (0.35 g, 57%) was obtained using (S)-(1-methylpyrrolidine-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate (0.32 g, 1.93 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =397.3 1 H NMR (400MHz, DMSO-d6): δ9.06-8.94(m, 1H), 7.65-7.12(m, 9H), 4.69-4.04(m, 7 H), 3.96-3.57(m, 2H), 3.28-2.98(m, 3H), 2.36-1.72(m, 4H), 1.28-1.22(m, 3H).

[0116] Example 6: (3R)-3-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (Compound 6) TIFF2026511228000027.tif31170

[0117] Compound 6 (0.30 g, 52%) was obtained using (R)-(1-methylpyrrolidine-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate (0.45 g, 1.45 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =397.2 1 H NMR (400MHz, CDCl3) δ8.81-8.78(m, 1H), 7.46-7.33(m, 9H), 4.52-4.49(m, 2H), 4.26-4.21(m, 2H), 4.02-3.98(m, 2H), 3.88-3. 61(m, 3H), 3.31-3.26(m, 1H), 3.19-3.17(m, 3H), 2.85-2.78(m, 1H), 2.28-2.14(m, 1H), 1.94-1.74(m, 1H), 1.27-1.24(m, 3H).

[0118] Example 7: 2-(2-(((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)ethyl)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (compound 7) TIFF2026511228000028.tif33170

[0119] Compound 7 (0.45 g, 47%) was obtained using 2-(1-methylpyrrolidine-2-yl)ethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.67 g, 1.78 mmol) in the same manner as in Example 1. MS:m / z[M-Br] - =463.2 1H NMR (400MHz, DMSO-d6): δ8.94(s, 1H), 7.58(d, J=6.8Hz, 1H), 7.51-7.30(m, 6H), 4.68-4.31(m, 1H), 4.30-4.20(m, 3H), 4.15-3.90(m, 3H), 3.75-3.64(m, 1H), 3.63-3.51(m, 1H), 3.26-2.97(m, 3H), 2.28-2.20(m, 2H), 2.08-2.00(m, 2H), 1.93-1.75(m, 2H), 1.25(t, J=6.8Hz, 3H).

[0120] Example 8: (3R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)-1-(2-methoxy-2-oxoethyl)-1-methylpyrrolidine-1-ium bromide (Compound 8) TIFF2026511228000029.tif37170

[0121] (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.30 g, 0.83 mmol) was dissolved in acetonitrile (10 mL), and then methyl 2-bromoacetate (0.19 g, 1.25 mmol) was added dropwise. The mixture was stirred under a nitrogen atmosphere at 25°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain compound 8 (66 mg, 16%). MS:m / z[M-Br] - =435.2 1 H NMR (400MHz, DMSO): δ8.99(d, J=6.0Hz, 1H), 7.58(dd, J=7.2, 1.2Hz, 1H), 7.52-7.46(m, 1H), 7.44-7.30(m, 5H), 4.58(d, J=21.6Hz, 2H) , 4.15-3.82(m, 3H), 3.76-3.59(m, 2H), 3.48-3.35(m, 1H), 3.27-3.12(m, 3H), 2.99-2.78(m, 1H), 2.37-2.11(m, 1H), 2.01-1.66(m, 1H).

[0122] Example 9: (3R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)-1-methyl-1-(2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)2-oxoethyl)pyrrolidine-1-ium bromide (compound 9) TIFF2026511228000030.tif33170

[0123] (R)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (0.30 g, 0.83 mmol) was dissolved in acetonitrile (10 mL), and then (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-bromoacetate (0.31 g, 1.25 mmol) was added dropwise. The mixture was stirred under a nitrogen atmosphere at 25°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC using acetonitrile and water containing 0.1% hydrogen bromide to obtain compound 9 (104 mg, 20%). MS:m / z[M-Br] - = 533.2 1 H NMR (400MHz, DMSO): δ8.96(d, J=8.4Hz, 1H), 7.84-7.16(m, 7H), 5.14(s, 2H), 4.57(d, J=15.6Hz, 2H), 4.17-3 .56(m, 5H), 3.45-3.34(m, 1H), 3.26-3.11(m, 3H), 2.90-2.73(m, 1H), 2.34-2.12(m, 4H), 1.98-1.78(m, 1H).

[0124] Example 10: (3R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)-1-methyl-1-(1-(2-(3-(nicotinoyloxy)propoxy)-2-oxoethyl)pyrrolidine-1-ium bromide (compound 10) TIFF2026511228000031.tif33170

[0125] (3R)-1-(carboxymethyl)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl-carbamoyl)oxy)methyl)-1-methylpyrrolidine-1-ium bromide (0.20 g, 0.48 mmol), 1-hydroxybenzotriazole (71 mg, 0.53 mmol), and 3-hydroxypropyl nicotinate (96 mg, 0.53 mmol) were dissolved in dichloromethane (20 mL), and then 3-(((ethylimino)methylene)amino)-N,N-dimethylpropane-1-amine hydrochloride (101 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by preparative HPLC using acetonitrile and water containing 0.1% hydrogen bromide to obtain compound 10 (50 mg, 16%). MS:m / z[M-Br] - = 583.8 1 H NMR (400MHz, DMSO): δ9.20-9.09(m, 1H), 9.01-8.90(m, 1H), 8.87-8.79(m, 1H), 8. 51-8.32(m, 1H), 7.68-7.60(m, 1H), 7.57-7.50(m, 1H), 7.50-7.42(m, 1H), 7.41-7. 24(m, 5H), 4.75-4.45(m, 3H), 4.45-4.29(m, 5H), 4.11-3.83(m, 8H), 3.38-3.27(m , 2H), 3.24-3.08(m, 3H), 2.90-2.76(m, 1H), 2.32-2.04(m, 3H), 1.92-1.76(m, 1H).

[0126] Experimental example Experimental Example 1: In vitro muscarinic M3 receptor antagonism

[0127] 1. Human muscarinic M3 receptor binding capacity test The affinity (Ki) of the compounds of the present invention for the human muscarinic acetylcholine M3 receptor was measured by a competitive filtration binding assay using the radiolabeled M3 receptor antagonist, [3H]-methylscopolamine.

[0128] Cell membrane protein (PerkinElmer) derived from CHO-K1 overexpressing the human muscarinic M3 receptor, [3H]-methylscopolamine, and test substances at various concentrations were cultured in 0.1 mL of Tris-HCl buffer at 25°C for 120 minutes, filtered by suction through a glass filter (Whatman GF / B), and then washed six times with 0.5 mL of chilled Tris-HCl buffer. 50 μL of Microscint 20 (Packard) was added to each well, and then incubated in an orbital shaker for 15 minutes. The radioactivity of [3H]-methylscopolamine adsorbed on the filter was measured using TopCount®. Nonspecific binding was evaluated in the presence of N-methylscopolamine at concentrations 200–300 times higher. To evaluate the binding ability of the example compounds to the muscarinic M3 receptor, the concentration of the test substance that inhibited the binding of the labeled ligand [3H]-methylscopolamine by 50% was measured according to the method of Cheng and Prusoff [Cheng and Prusoff, Biochem. Pharmacol., Vol. 22, p. 3099, 1973]. 50 The dissociation constant (Ki) was calculated from the given values. A lower dissociation constant (Ki) indicates stronger binding ability of the compound to the human muscarinic M3 receptor.

[0129] The binding ability of each test substance to the M3 receptor is shown in Table 1 below. [Table 1]

[0130] As can be seen from Table 1 above, the compounds of the present invention exhibit excellent IC2C at the nM level for the human muscarinic M3 receptor. 50 It was confirmed that it has a value.

[0131] 2. Human muscarinic M3 receptor antagonist study We evaluated the antagonistic effect on the human muscarinic M3 receptor using CHO-K1 cells (CHO-K1 mt aequorin, PerkinElmer) into which the M3 receptor was introduced.

[0132] Recombinant cells, grown in antibiotic-free medium 18 hours prior to the test, were gently flushed with PBS-EDTA (5 mM EDTA) to separate them, recovered by centrifugation, and resuspended in buffer (DMEM / HAM's F12 containing HEPES + 0.1% BSA protease). The cells were cultured at room temperature for at least 4 hours using Coelenterazine h (Molecular Probes). Before evaluating the compounds, dose-response curves were obtained using a reference compound (4-DAMP).

[0133] For evaluation, 50 μL of cell suspension was injected into 50 μL of test material or reference compound placed in a 96-well plate. Luminescence was recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000).

[0134] After the first injection, incubate for 15 minutes, then in 100 μL of a mixture of cell suspension and test compound for antagonist testing, EC 80 100 μL of a reference agonist (acetylcholine) at a concentration equivalent to the target was injected. Luminescence was recorded using FDSS6000.

[0135] The antagonistic activity of the test compound is compared to the EC of the reference agonist (acetylcholine). 80 It is calculated as the inhibition rate of reference activity at a given concentration, followed by IC 50 The values ​​were calculated. The M3 receptor antagonistic activity for each test substance is shown in the table below. [Table 2]

[0136] Experimental Example 2: Evaluation of drug efficacy in a pilocarpine-induced mouse hyperhidrosis model In a pilocarpine-induced hyperhidrosis model, an iodine-starch sweat test was performed to confirm the effectiveness of the test substance in suppressing sweating.

[0137] Six-week-old male ICR mice (ORIENT BIO INC.) were purchased, allowed to acclimate for one week, and then divided into groups based on body weight. The test groups are shown in Table 3 below. [Table 3]

[0138] Vehicle: Anhydrous ethanol Four hours before pilocarpine administration, the test substance was prepared in 20% anhydrous ethanol (Daejung) and 10 μL was applied to the soles of both hind limbs of mice. Four hours after application of the test substance, an anesthetic (rompum:ketamine = 1:4) was administered intraperitoneally, followed by intraperitoneal administration of pilocarpine (5 mg / kg / 5 mL) to the anesthetized animals. Iodine (Sigma-Aldrich) was dissolved in 3.5% ethanol and applied to the soles of both hind limbs using a brush. After drying for approximately 1 minute, starch (Milipore) was suspended in 10% castor oil (Sigma-Aldrich) and applied to the same areas using a brush. Ten minutes after pilocarpine administration, photographs of the sole skin were taken, and then the number of sweat spots per food pad (sweat spots / food pad) for each subject was analyzed. Sofpyronium bromide (JHCHEM) was used as the positive control group.

[0139] All data obtained from the experiment were expressed as mean ± standard error, and all results were analyzed using one-way ANOVA with SPSS (version 20, IBM SPSS Statistics, USA). Significance was verified by post-hoc testing using the LSD test.

[0140] The test results are shown in Table 4 below. [Table 4]

[0141] ## p<0.01 vs normal group; ** p<0.01 vs derived group (one-way ANOVA, LSD post-hoc test)

[0142] The number of sweat spots was 17.00±11.90 in the normal group (vehicle) that did not receive pilocarpine, and 116.88±49.54 in the sweat-induced group that received pilocarpine, indicating the induction of hyperhidrosis (p<0.01).

[0143] The number of sweat spots in the group administered compound 1 and the group administered compound 3 was 32.25±6.14 and 37.50±13.02, respectively, which was significantly reduced compared to the sweat-inducing group (p<0.01; see Table 4 and Figure 1).

[0144] Furthermore, it was confirmed that the number of sweat spots in the positive control group (sofpyronium) at the same concentration was 42.13 ± 8.35, revealing that the compound of the present invention exhibits at least equivalent or greater sweat-inhibiting ability compared to the positive control group (sofpyronium).

[0145] The present invention has been described herein based on exemplary embodiments. However, it should be understood that the present invention is not limited to the embodiments described, and that all changes, modifications, alterations, and substitutions that do not depart from the spirit and essential features of the invention are within the scope of the invention.

Claims

1. Formula 1 below [Formula 1] A compound represented by, its stereoisomer, its hydrate, or its solvate, In formula 1, R １ and R ２ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, nitro, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, C １ -C ６ alkylamino, C １ -C ６ dialkylamino, and aminocarbonyl R ３ is hydrogen or C １ ~C ６ It is alkyl, R ４ It does not exist, or it is -A, -OC(O)-A, -O-A, or -C(O)-A. A is a 5-6 member heteroaryl or 5-6 member heterocycloalkyl compound containing 1 to 3 heteroatoms selected from N, O, or S, where the 5-6 member heteroaryl and 5-6 member heterocycloalkyl compounds are oxo, halogen, hydroxy, cyano, amino, or C １ ~C ６ Alkyl, or C １ ~C ６ It may be arbitrarily substituted with an alkoxy, n and m are independent integers between 0 and 3. k is an integer between 1 and 3. p is an integer from 1 to 5, and X － This refers to a monovalent anion, a compound, its stereoisomer, its hydrate, or its solvate.

2. R １ and R ２ However, each can independently be hydrogen, halogen, hydroxyl, cyano, or C. １ ~C ３ It is an alkoxy, and The compound according to claim 1, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, wherein n and m are independently 0, 1, or 2.

3. R ３ C １ ~C ３ A compound according to claim 1, which is alkyl, a stereoisomer thereof, a hydrate thereof, or a solvate thereof.

4. p is an integer between 1 and 3, R ４ However, it does not exist, or it is -A or -OC(O)-A, and A is pyridinyl, 2-oxo-1,3-dioxol-4-yl, or 1,3-dioxol-4-yl, and is halogen, hydroxy, cyano, amino, C １ ~C ３ Alkyl, or C １ ~C ３ The compound according to claim 1, which may be optionally substituted with an alkoxy, a stereoisomer thereof, a hydrate thereof, or a solvate thereof.

5. X － The compound according to claim 1, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate.

6. X － The compound according to claim 5, wherein bromide is a stereoisomer thereof, a hydrate thereof, or a solvate thereof.

7. The above compound belongs to the following group A compound according to claim 1, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, selected from the above.

8. A pharmaceutical composition for the prevention or treatment of muscarinic acetylcholine receptor-mediated diseases, comprising a compound according to any one of claims 1 to 7, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the muscarinic acetylcholine receptor-mediated disorder is selected from the group consisting of hyperhidrosis, hypersalivation, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, urinary incontinence, overactive bladder syndrome, gastroesophageal reflux disease, and irritable bowel syndrome.

10. The pharmaceutical composition according to claim 9, wherein the muscarinic acetylcholine receptor-mediated disorder is hyperhidrosis.

11. A method for preventing or treating a muscarinic acetylcholine receptor-mediated disease, comprising the step of administering or topically applying a compound according to any one of claims 1 to 7, a stereoisomer thereof, a hydrate thereof, or a solvate thereof.

Images