Body fluid conditioning agent, composition for body fluid conditioning, and use of compound

Abstract

A body fluid conditioning agent comprising a compound represented by formula (I), an ester thereof, or a salt thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a body fluid regulator, a combination agent for body fluid regulation, and uses of a compound. Background Art

[0002] Retention of excess body fluid is a concomitant symptom of many diseases such as heart failure, hypertension, liver cirrhosis, kidney disease, lymphedema, and lipedema. Especially in patients with loss of residual renal function, the daily urine volume is less than 200 ml, and the efficacy of diuretics is weakened. Treatment methods for loss of residual renal function are dialysis and kidney transplantation. However, in about one-third of patients, water removal by dialysis is insufficient (see Non-Patent Document 1). Regarding kidney transplantation, not only are kidney donors limited, but also the number of cases where kidney transplantation can be performed is extremely small. In addition to diuretics, dialysis therapy, and kidney transplantation, other body fluid regulators are also needed in clinical practice.

[0003] Local tissue interstitial fluid retention (edema) is a common clinical manifestation of lymphedema and lipedema. Lymphedema is caused by obstruction of lymphatic return, resulting in retention of body fluid around blood vessels and in subcutaneous tissue. Regarding the excess tissue fluid in lipedematous tissue, it has been reported that it may be caused by various factors such as increased vascular permeability due to microvascular disorders and insufficient drainage of interstitial fluid through lymphatic vessels (see Non-Patent Document 2). Sweat glands receive blood supply from cutaneous perforators of blood vessels, and blind-ended micro-lymphatic vessels parallel to the blood supply originate from the dermal papillary layer and drain interstitial fluid into veins. Sweating can improve the excess tissue fluid in the subcutaneous tissue of lymphedema and lipedema caused by excessive vascular permeability and insufficient lymphatic drainage.

[0004] According to Non-Patent Document 3, sweating as a physiological phenomenon has the ability to excrete an amount of water exceeding that excreted by urine. That is, sweating is expected to become a new body fluid regulation method to replace diuretics, dialysis therapy, and kidney transplantation. In-depth research has shown that sweating is regulated by the M3 muscarinic receptor. As disclosed in Non-Patent Document 4, a sweating test using pilocarpine (which is a non-selective agonist of the M3 muscarinic receptor) as a method for diagnosing diseases has been widely used clinically.

[0005] [Patent Document]

[0006] Patent Document 1: International Publication No. 2015 / 186821 (WO2015186821A)

[0007] [Non-Patent Document]

[0008] Non-Patent Document 1: Michelle M.Y. Wong, et al., Interdialytic Weight Gain: Trends, Predictors, and Associated Outcomes in the International Dialysis Outcomes and Practice Patterns Study (DOPPS), Am J Kidney Dis., 69(3), 367 - 379, 2017 (Michelle M.Y. Wong, et al., Interdialytic Weight Gain: Trends, Predictors, and Associated Outcomes in the International Dialysis Outcomes and Practice Patterns Study (DOPPS), American Journal of Kidney Diseases, 69(3), 367 - 379, 2017)

[0009] Non-Patent Document 2: Allen M, Michael Schwartz M, and Herbst K.L., Interstitial Fluid in Lipedema and Control Skin, Women’s Health Reports, 1(1), 480 - 487, 2020 (Allen M, Michael Schwartz M, and Herbst K.L., Interstitial Fluid in Lipedema and Control Skin, Women's Health Reports, 1(1), 480 - 487, 2020)

[0010] Non-Patent Document 3: Lindsay B. Baker, Physiology of sweat gland function: The roles of sweating and sweat composition in human health, Temperature, 6(3), 211 - 259, 2019 (Lindsay B., Physiology of sweat gland function: The roles of sweating and sweat composition in human health, Temperature, 6(3), 211 - 259, 2019)

[0011] Non-Patent Document 4: Pamela B. Davis, Cystic Fibrosis Since 1938, American Journal of Respiratory and Critical Care Medicine, 173, 475 - 482, 2006 (Pamela B. Davis, Cystic Fibrosis Since 1938, American Journal of Respiratory and Critical Care Medicine, 173, 475 - 482, 2006) Summary of the Invention

[0012] Problems to be Solved by the Invention

[0013] Currently, there is no agonist that selectively stimulates the M3 muscarinic receptor, and there are also concerns that the stimulation of non-selective muscarinic receptors will produce side effects. Moreover, under the stimulation of agonists, sweating often occurs, which affects daily life and causes inconvenience. If the sweating time can be controlled more flexibly, excessive fluid retention can be improved without affecting the quality of life.

[0014] In view of the above actual situation, the present invention is made, and its purpose is to provide a body fluid regulator, a body fluid regulation combination agent, and the use of a compound that can control the sweating time more flexibly.

[0015] Means for Solving the Problems

[0016] The compound disclosed in Patent Document 1 is a positive allosteric modulator (PAM) of the M3 muscarinic receptor. The present inventors found that when this compound is used alone, it does not affect sweating, but when combined with an M3 muscarinic receptor agonist, it promotes sweating in a dose-dependent manner, thus completing the present invention.

[0017] The body fluid regulator of the first aspect of the present invention comprises a compound represented by formula (I), its ester, or its salt,

[0018] (Chemical Formula 1)

[0019]

[0020] The body fluid regulator according to the first aspect of the present invention can be used in combination with a diuretic in an individual.

[0021] The body fluid regulator according to the first aspect of the present invention can be used in combination with an M3 muscarinic receptor agonist in an individual.

[0022] The body fluid regulator according to the first aspect of the present invention can be used in combination with heat stimulation or thermogenic stimulation in an individual.

[0023] The individual may suffer from a disease accompanied by excessive fluid retention.

[0024] The disease may be heart failure, hypertension, cirrhosis, kidney disease, nephrotic syndrome, renal failure, diabetes, drug-induced excessive fluid retention, lymphedema, or lipedema.

[0025] When the disease is renal failure, the body fluid regulator according to the first aspect of the present invention can be used to delay the start time of dialysis therapy.

[0026] The individual may suffer from a disease accompanied by dry skin or itching.

[0027] The disease may be senile xerosis, atopic dermatitis, psoriasis, ichthyosis, radiodermatitis, actinic keratosis, senile keratosis, kidney disease, renal failure or diabetes.

[0028] The combination agent for body fluid regulation according to the second aspect of the present invention comprises the compound represented by formula (I), its ester or its salt, and a diuretic.

[0029] (Chemical formula 2)

[0030]

[0031] The combination agent for body fluid regulation according to the third aspect of the present invention comprises the compound represented by formula (I), its ester or its salt, and an M3 muscarinic receptor agonist.

[0032] (Chemical formula 3)

[0033]

[0034] The use of the compound according to the fourth aspect of the present invention, which is the use of the compound represented by formula (I), its ester or its salt in the preparation of a body fluid regulator.

[0035] (Chemical formula 4)

[0036]

[0037] Effects of the invention

[0038] According to the present invention, it is possible to more flexibly control the sweating time. Description of the drawings

[0039] Figure 1 is a graph showing the amount of sweating measured in Test Example 1.

[0040] Figure 2 is a graph showing the amount of sweating measured in Example 1.

[0041] Figure 3 is a graph showing the amount of sweating measured in Example 2, where Figure 3 A, Figure 3 B, Figure 3 C and Figure 3 D are the results of administering 0, 10, 30 and 100 mg / kg of the compound, respectively. Detailed implementation manners

[0042] Embodiments of the present invention will be described with reference to the accompanying drawings. In addition, the present invention is not limited to the following embodiments and drawings. In the following embodiments, expressions such as "having", "comprising", or "containing" also include the meanings of "consisting of..." or "constituted by...".

[0043] [Embodiment]

[0044] The body fluid regulator according to the present embodiment contains the compound represented by formula (I), its ester, or its salt.

[0045] (Chemical formula 5)

[0046]

[0047] This compound is a PAM for the M3 muscarinic receptor. Generally, a PAM is a compound that binds to an allosteric site different from the ligand binding site, mainly by causing a structural change in the receptor, increasing the binding force between the endogenous agonist and the receptor, and thus having the effect of changing the agonist signal level. A PAM itself does not exhibit an agonist effect in vivo, but enhances the effect of the agonist.

[0048] In this specification, the compound of formula (I) may sometimes be described only in one form of the isomer, but the above compound of the present embodiment also includes other isomers, and also includes isolated isomers, or mixtures thereof. In addition, the compound of formula (I) may have optical isomers based on asymmetric carbon atoms or axial asymmetry. The above compound according to the present embodiment also includes isolated optical isomers of the compound of formula (I), or mixtures thereof.

[0049] In addition, the present embodiment also includes pharmaceutically acceptable prodrugs of the compound represented by formula (I). A pharmaceutically acceptable prodrug refers to a compound that can be decomposed by a solvent or converted into groups such as amino, hydroxyl, and carboxyl groups under physiological conditions.

[0050] The salts of the compound represented by the above formula (I) are not particularly limited as long as they are pharmacologically acceptable salts, and can be either acidic salts or alkaline salts. Examples of salts include: alkali metal salts such as lithium salts, sodium salts, and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, and phosphates; and organic acid salts such as formates, acetates, oxalates, propionates, hexanoates, cyclopentanepropionates, glycolates, pyruvates, lactates, malonates, succinates, malates, fumarates, tartrates, dibenzoyl tartrates, xylolyl tartrates, citrates, benzoates, o-(4-hydroxybenzoyl)benzoates, cinnamates, mandelates, methanesulfonates, ethanesulfonates, 1,2-ethanedisulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, 2-naphthalenesulfonates, p-toluenesulfonates, aspartates, camphorsulfonates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, glucuronates, glutamates, hydroxynaphthoates, salicylates, stearates, trifluoroacetic acid (TFA) salts, maleates, dimaleates, and muconates, etc. Preferably, the body fluid regulator according to the present embodiment includes the dimaleate represented by formula (I).

[0051] The esters of the compound represented by the above formula (I) are not particularly limited as long as they are pharmacologically acceptable esters, and examples include carbonates, phosphates, nitrates, sulfates, borates, and sulfonates, etc.

[0052] In addition, the present embodiment also includes various hydrates, solvates, and polymorphic substances of the compound of formula (I) and its salts. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0053] The compound of formula (I), its esters, and its salts can be prepared by applying various known synthetic methods based on the characteristics of their basic structures or substituent types. At this time, depending on the type of functional group, it is sometimes effective to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. After introducing the protecting group and carrying out the reaction, the protecting group is removed as needed, whereby the desired compound can be obtained.

[0054] Herein, a representative preparation method of the compound of formula (I) and the compound of formula (a) as its raw material will be described. In addition, the preparation method of the above compound is not limited to the examples shown below.

[0055] (First Preparation Method)

[0056] (Chemical Formula 6)

[0057]

[0058] (In the formula, R represents an alkyl group having 1 to 6 carbon atoms. The same applies hereinafter)

[0059] The first preparation method is a method for preparing the compound of formula (I) by deprotecting the compound of formula (a). In the first preparation method, an equal amount of the compound of formula (a) and the deprotecting reagent are used or one of them is used in excess, and in an inert solvent for the reaction or without a solvent, from cooling to heating under reflux, it is usually stirred for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, but may include: alcohols such as methanol, ethanol and n-propanol, N,N-dimethylformamide and tetrahydrofuran. Examples of the deprotecting reagent are not particularly limited, and may include: bases such as aqueous sodium hydroxide solution and aqueous potassium hydroxide solution, and acids such as hydrochloric acid and trifluoroacetic acid.

[0060] (Second preparation method)

[0061] (Chemical formula 7)

[0062]

[0063] (In the formula, L 1 represents a leaving group. The same applies hereinafter)

[0064] The second preparation method is a preparation method of the compound of formula (a) (which is the raw material of the compound of formula (I)). Herein, examples of L 1 include Cl, etc.

[0065] (First step)

[0066] In this step, the compound of formula (d) is obtained from the compound of formula (b) and the compound of formula (c) through an amidation reaction. In this reaction, an equivalent amount of the compound of formula (b) and the compound of formula (c) is used or an excess of one of them is used, and their mixture is stirred in a solvent inert to the reaction, in the presence of a condensing agent, from cooling to heating, preferably at -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited and may include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and cyclopentyl methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, water, and mixtures thereof. Examples of the condensing agent may include: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diphenylphosphoryl azide, phosphorus oxychloride, and N-[({[(1Z)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethanaminium hexafluorophosphate (COMU), etc. Preferably, an additive (such as 1-hydroxybenzotriazole) is used in the reaction. The reaction can also be carried out in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine, or inorganic bases such as potassium carbonate, sodium carbonate, and potassium hydroxide.

[0067] Alternatively, a method of converting the carboxylic acid (c) into a reactive derivative and then reacting it with the amine (b) can also be adopted. Examples of the reactive derivative of the carboxylic acid may include: acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, etc., and active esters obtained by condensing with 1-hydroxybenzotriazole, etc. The reaction of these reactive derivatives with the compound (b) can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, from cooling to heating, preferably at -20°C to 60°C.

[0068] (Second step)

[0069] In this step, the compound of formula (f) is prepared by the reaction of the compound of formula (d) with the compound of formula (e). In this reaction, an equal amount of compound (d) and compound (e) is used or one of them is used in excess, and the mixture is stirred in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably at 0 °C to 80 °C, usually for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and may include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. The reaction can also be carried out in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine, or inorganic bases such as potassium carbonate, sodium carbonate, and potassium hydroxide.

[0070] (Third step)

[0071] In this step, an acetoxymethyl group is introduced into the 5-position of the thiazole of the compound of formula (f) to prepare the compound of formula (g). For example, in this reaction, an aqueous formaldehyde solution or paraformaldehyde is allowed to act on the compound of formula (f) in an acetic acid solvent, and the reaction is carried out at room temperature or under heating, or at room temperature or under reflux. Alternatively, instead of the acetic acid solvent, the reaction can also be carried out by adding acetic acid in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers. In addition, anhydrous acetic acid can also be added for the reaction.

[0072] (Fourth step)

[0073] In this step, the compound of formula (a) is prepared by reacting the compound of formula (h) with the compound of formula (g) under basic conditions. For example, this reaction is carried out in an organic solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, and in the presence of an organic base such as triethylamine and N,N-diisopropylethylamine, and the compound of formula (h) is allowed to act on the compound of formula (g). In addition, the compound of formula (h) can be used in excess instead of the organic base. The reaction can be carried out under cooling or at room temperature, at room temperature or under heating, or at room temperature or under reflux. In addition, by further adding the compound of formula (h) to the reaction mixture of the third step, the compound of formula (a) can be directly obtained without separating the compound of formula (g).

[0074] The compound of formula (I) is isolated and purified as a free compound, its salts, hydrates, solvates or polymorphic forms. The salts of the compound of formula (I) can also be prepared by conventional methods. Isolation and purification are carried out using conventional chemical operations, such as extraction, fractional crystallization and various types of fractional chromatography. The various isomers can be prepared by selecting appropriate starting compounds, or can be separated by taking advantage of the differences in the physicochemical properties between the isomers. For example, optical isomers can be obtained by the general optical resolution methods of racemates (e.g., fractional crystallization of diastereomeric salts directed to optically active bases or acids and chromatography using chiral columns, etc.). In addition, optical isomers can also be prepared from optically active starting compounds.

[0075] The body fluid regulator of the present embodiment contains the compound represented by the above formula (I), its ester or its salt (hereinafter also referred to as "compound, etc.") as an active ingredient, and may also contain other pharmaceutically acceptable components. Other pharmaceutically acceptable components are, for example, excipients, lubricants, binders and disintegrants in solid preparations, or solvents, cosolvents, suspending agents and tonicity agents, buffers and analgesics in liquid preparations. In addition, additives such as preservatives, antioxidants, coloring agents and sweeteners can be formulated into the body fluid regulator as needed.

[0076] Excipients include, for example: lactose, sucrose, D-mannitol, starch, crystalline cellulose and light anhydrous silicic acid, etc. Lubricants include, for example: magnesium stearate, calcium stearate, talc and colloidal silica, etc. Binders include, for example: crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone, etc. Disintegrants include, for example: starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, etc.

[0077] Solvents include, for example: water for injection, ethanol, propylene glycol and polyethylene glycol, etc. Cosolvents include, for example: polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate, etc. Suspending agents are surfactants, hydrophilic polymers, etc., and include, for example: stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, etc.

[0078] Tonic agents include, for example, sodium chloride, glycerol, D-mannitol, etc. Buffering agents include, for example, buffer solutions of phosphates, acetates, carbonates, and citrates, etc. Analgesic agents include, for example, benzyl alcohol, etc. Preservative agents include, for example, parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid, etc. Antioxidant agents include, for example, sulfites and ascorbic acid, etc.

[0079] The body fluid regulator according to the present embodiment is administered to a human or non-human animal. The animal is preferably a mammal, and more specifically, examples include dogs, cats, cows, pigs, horses, sheep, deer, etc. There is no particular limitation on the administration route of the body fluid regulator to humans, etc. The body fluid regulator can be used as an injection, and preferably as an oral preparation. The body fluid regulator is prepared by known methods and provided in the form of a liquid, lozenge, granule, fine granule, powder, tablet, capsule, etc.

[0080] The dosage of the body fluid regulator is appropriately determined according to the age, weight, symptoms, etc. of the administered individual. The body fluid regulator is administered in such a way that the above-mentioned compounds, etc. become an effective amount. The so-called effective amount refers to the amount required to delay, inhibit, prevent, reverse, or cure the progression of symptoms related to diseases accompanied by excessive body fluid retention in the administered individual.

[0081] The body fluid regulator according to the present embodiment can enhance the effect of food-induced thermogenesis and promote sweating caused by the stimulation of the M3 muscarinic receptor. Therefore, even if the body fluid regulator is administered alone to an individual without combining with an exogenous heat stimulus or a thermogenic stimulus, a certain sweating effect can be obtained. Since the body fluid regulator has the characteristic of promoting sweating depending on the stimulus, the duration of sweating can be controlled by giving the timing of food-induced thermogenesis, etc.

[0082] Preferably, the body fluid regulator according to the present embodiment is used in combination with a diuretic or an M3 muscarinic receptor agonist in an individual. For example, when used in combination with a diuretic whose efficacy is reduced due to renal dysfunction, an additional effect can be obtained. In addition, by using the body fluid regulator in combination with a threshold dose of an M3 muscarinic receptor agonist, sweating can occur while avoiding the side effects and inappropriate timing of the M3 muscarinic receptor agonist. Furthermore, by using it in combination with a diuretic or an M3 muscarinic receptor agonist, sweating can be promoted without having a patient with a decreased physical strength (such as a patient with uremia, etc.) exercise or take a bath.

[0083] There is no particular limitation on the diuretics, and examples thereof include, for example: loop diuretics such as furosemide, bumetanide, torasemide, piretanide, and azosemide; thiazide diuretics such as trichlormethiazide, hydrochlorothiazide, and benzylhydrochlorothiazide; thiazide-like diuretics such as chlorthalidone, mefruside, indapamide, tripamide, and meticrane; potassium-sparing diuretics such as spironolactone, triamterene, and potassium canrenoate; carbonic anhydrase inhibitor diuretics such as acetazolamide; osmotic diuretics such as isosorbide, concentrated glycerol, fructose, D-mannitol; and mozavaptane hydrochloride, etc.

[0084] The M3 muscarinic receptor agonist may be an M3 muscarinic receptor agonist that directly activates the M3 muscarinic receptor, or may be a cholinesterase inhibitor that indirectly stimulates the M3 muscarinic receptor. Examples of the M3 muscarinic receptor agonist include pilocarpine, cevimeline, carbachol, bethanechol, acetylcholine, methacholine, and carpronium, etc. Examples of the cholinesterase inhibitor include donepezil, galantamine, rivastigmine, and distigmine, etc.

[0085] "Combined use" means administering the body fluid regulator according to the present embodiment and the aforementioned diuretic or M3 muscarinic receptor agonist to the same patient within a specified period. In the case of combined use, the body fluid regulator may be administered simultaneously with the diuretic or M3 muscarinic receptor agonist, but may also be administered separately at staggered times, for example, administering one when the effect of the other still persists. In the case of combined use, the administration routes of the body fluid regulator and the diuretic or M3 muscarinic receptor agonist may be the same or different. As the modes of combined use, for example, there may be mentioned: administration of a single preparation obtained by formulating the body fluid regulator and the diuretic or M3 muscarinic receptor agonist before administration, simultaneous administration of two preparations obtained by separately formulating the body fluid regulator and the diuretic or M3 muscarinic receptor agonist via the same administration route, administration of the two preparations via the same administration route with a time difference, simultaneous administration of the two preparations via different administration routes, and administration of the two preparations via different administration routes with a time difference. For example, in the case of combined use, there is a protocol for the respective dosages and administration methods of the body fluid regulator and the diuretic or M3 muscarinic receptor agonist according to regulations, and within a specified time period, the body fluid regulator and the diuretic or M3 muscarinic receptor agonist are administered.

[0086] The body fluid regulator according to the present embodiment may also be used in combination with heat stimulation or thermogenic stimulation to an individual. Heat stimulation refers to a physical stimulation that provides heat, for example, an individual using a heating device, a heater, a foot warmer, etc., taking a warm bath or a hot bath, using a sauna, irradiating an individual with infrared rays, and setting the environmental temperature where the individual is located to a higher level. Thermogenic stimulation refers to a stimulation that generates metabolic heat, for example, an individual's diet and exercise, etc. The timing of heat stimulation or thermogenic stimulation to an individual is not particularly limited as long as the heat stimulation or thermogenic stimulation occurs within the effective period of the body fluid regulator administered to the individual, and it may be performed before or after administering the body fluid regulator to the individual. Depending on the body fluid regulator, the amount and time of sweating can be controlled by the intensity of the heat stimulation or thermogenic stimulation and the application time of the heat stimulation or thermogenic stimulation.

[0087] The aforementioned individual may suffer from a disease accompanied by excessive body fluid retention. Excessive body fluid retention includes, for example, ascites and edema (cardiac edema, renal edema, hepatic edema, drug-induced edema, lipedema, lymphedema, edema caused by peripheral vascular disorders, etc.). Examples of such diseases include heart failure, hypertension, liver cirrhosis, kidney disease, nephrotic syndrome, renal failure, diabetes, drug-induced excessive body fluid retention, lipedema, or lymphedema, etc.

[0088] In addition, on the judgment criteria for the start of dialysis treatment for renal failure, fluid accumulation (generalized edema, severe hypoproteinemia, or pulmonary edema) and fluid abnormalities (uncontrolled electrolyte / acid-base imbalance) are important. Through sweating, water and electrolytes contained in sweat are excreted from the body, which is expected to improve fluid accumulation and fluid abnormalities and delay the start time of dialysis treatment. Therefore, for an individual with renal failure, which is a disease accompanied by excessive fluid retention, the body fluid regulator of the present embodiment can be used to delay the start time of dialysis treatment. In addition, "delaying the start time of dialysis treatment" means delaying the start time of dialysis treatment for an individual compared to when the body fluid regulator is not administered.

[0089] Xerosis, which is common in aging and many diseases, is mainly caused by a decrease in the water content of the epidermis of the skin. Since the epidermis has no blood vessels, the water content of the epidermis is maintained by the movement of water from the dermis, the natural moisturizing factors contained in the epidermis, and the physical barrier of the outermost stratum corneum (D. Barco and A. Gimenez-Arnau, Xerosis: a Dysfunction of the Epidermal Barrier, Actas Dermosifiliogr, 99, 671-82, 2008). Before sweat reaches the skin surface, the water content of the epidermis is first increased (Gerrett N., et al., Sweat from gland to skin surface: production, transport, and skin absorption, J Appl Physiol 125, 459-469, 2018). Natural moisturizing factors such as urea, amino acids, lactic acid, and inorganic salts contained in sweat are also replenished. For example, urea, one of the natural moisturizing factors contained in sweat, is a hygroscopic molecule that not only plays an important role in replenishing the water content of the stratum corneum but also improves the skin barrier function including antimicrobial defense by regulating gene expression related to the differentiation and proliferation of keratinocytes and the production of antimicrobial peptides, and is thus essential for the integrity of the epithelial layer (Piquero-Casals J., et al., Urea in Dermatology: A Review of its Emollient, Moisturizing, Keratolytic, Skin Barrier Enhancing and Antimicrobial Properties, Dermatol Ther. (Heidelb), 11, 1905-1915, 2021). That is, the promotion of sweating by the body fluid regulator of the present embodiment improves skin dryness by replenishing both water and moisturizing components. Therefore, the aforementioned individual may suffer from a disease accompanied by skin dryness or itching.Examples of such diseases include: senile xerosis, atopic dermatitis, psoriasis, ichthyosis, radiation dermatitis, actinic keratosis, senile keratosis, (chronic) kidney disease, renal failure, and diabetes, etc.

[0090] Many drugs are excreted via the kidneys. When a drug is administered to an individual with renal dysfunction, there are problems in drug metabolism such as elevated blood concentrations and even safety issues. As shown in Example 3 below, the above-mentioned compounds and the like have the characteristic of low excretion rate from the kidneys. Therefore, the body fluid regulator of the present embodiment is easy to control the blood concentration and is safe even when used for the excretion of excess body fluid retention in individuals with reduced renal function (such as kidney disease, renal failure, diabetic nephropathy, and intractable nephropathy, etc.), and for the improvement of dryness, repair of the skin barrier, and suppression of itching related to skin dryness and itching associated with renal failure or chronic kidney disease.

[0091] In addition, the main reason why individuals with decreased renal function cannot comply with the restriction of water intake is thirst. The individual's intake of water exceeding the limit is one of the causes of body fluid retention. As disclosed in International Patent Application Publication No. WO2022 / 054965, the compound promotes saliva secretion. By promoting saliva secretion to improve thirst, it also helps individuals with decreased renal function to comply with the amount of water they intake.

[0092] In addition, in other embodiments, a body fluid regulating combination agent is provided, which comprises the above-mentioned compounds and the like and a diuretic or an M3 muscarinic receptor agonist. The body fluid regulating combination agent is obtained by combining the above-mentioned compounds and the like as active ingredients with a diuretic or an M3 muscarinic receptor agonist. The body fluid regulating combination agent can be a combined medication preparation in which the above-mentioned compounds and the like are combined with a diuretic or an M3 muscarinic receptor agonist and administered.

[0093] The "body fluid regulating combination agent" means: a set provided by including the above-mentioned compounds and the like and a diuretic or an M3 muscarinic receptor agonist as a compound agent, and preparing them as independent preparations respectively. When the body fluid regulating combination agent is a compound agent, the above-mentioned compounds and the like and a diuretic, or the above-mentioned compounds and the like and an M3 muscarinic receptor agonist, can be prepared by a conventional method of mixing a plurality of drugs to form a compound agent. The compound agent can also contain any component other than the above-mentioned compounds and the like and a diuretic or an M3 muscarinic receptor agonist. The any component is other pharmacologically acceptable components that can be included in the above-mentioned body fluid regulator. The form of the compound agent is arbitrary, for example, liquid, solid, semi-solid, powder, etc. The compound ratio of the above-mentioned compounds and the like and a diuretic or an M3 muscarinic receptor agonist only needs to be set to an appropriate compound ratio that can exert their respective effects.

[0094] In the case where the combination agent for body fluid regulation in the present embodiment is a kit including a first preparation containing the above compound and the like and a second preparation containing a diuretic or an M3 muscarinic receptor agonist, the first preparation and the second preparation may be in the same form or in different forms. In addition, the first preparation and the second preparation may be preparations having the same administration route or administration method, or may be preparations having different administration routes or administration methods. For example, both the first preparation and the second preparation may be oral preparations or parenteral preparations, or the first preparation may be an oral preparation while the second preparation is a parenteral preparation, or the first preparation may be a parenteral preparation while the second preparation is an oral preparation. The first preparation may also contain any components other than the above compound and the like. The second preparation may also contain any components other than a diuretic or an M3 muscarinic receptor agonist. The optional components are other pharmacologically acceptable components that can be included in the above body fluid regulator. Further, the second preparation may contain both a diuretic and an M3 muscarinic receptor agonist.

[0095] In other embodiments, there is provided the use of a compound represented by formula (I), an ester thereof or a salt thereof in the preparation of a body fluid regulator. In other embodiments, there is provided a method for regulating body fluid. The method includes the step of administering the above compound, an ester thereof or a salt thereof to an individual suffering from a disease accompanied by excessive body fluid retention. Additionally, in other embodiments, there is provided a compound, an ester thereof or a salt thereof for treating a disease accompanied by excessive body fluid retention.

[0096] The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples.

[0097] Examples

[0098] Test Example 1: Investigation of the sweating action threshold of pilocarpine

[0099] CD (SD) rats (male, 7 weeks old, produced by The Jackson Laboratory Japan, Inc.) were acclimated to the environment for 1 week. The feed during the breeding period was CRF-1 (manufactured by Oriental Yeast Co., Ltd.) sterilized by γ-ray irradiation of 30 kGy or more, and the drinking water was tap water added with chlorine (4 to 6 ppm). The feed and drinking water were freely available. When in use, pilocarpine hydrochloride (manufactured by FUJIFILM Wako Pure Chemical Corporation, Japan) was dissolved in physiological saline to prepare a dosing solution. The dosing amounts were 0 (physiological saline), 1, 3 or 10 mg / kg (n = 3 to 4).

[0100] Inject 0.5 mL of a mixture of three anesthetics corresponding to 100 g of rat body weight into the abdominal cavity of the rats. After the disappearance of the righting reflex, administer physiological saline or the above-mentioned administration solution subcutaneously. After 5 minutes, attach filter paper of a pre-weighed weight to the palm parts of the four limbs and tightly wrap with plastic wrap or the like. Absorb the sweat secreted within 30 minutes with the filter paper and recover it.

[0101] (Result)

[0102] The weight of the sweat recovered within 30 minutes (sweating amount) is shown in Figure 1 . Compared with the 0 mg / kg group, a significantly higher sweating effect was observed in the 10 mg / kg group (one-tailed T-test, *p < 0.05). 3 mg / kg was judged to be the threshold of the sweating effect of pilocarpine.

[0103] Example 1: Investigation of the sweating effect of the compound

[0104] Investigate the sweating effect of the compound shown in the above formula (I) (3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid dimaleate).

[0105] When in use, suspend the compound in a 0.5 w / v% methylcellulose 400 solution (hereinafter referred to as the MC solution, manufactured by FUJIFILM Wako Pure Chemical Corporation, Japan) to prepare the administration solution. The administration dosage is 0 (MC solution), 10, 30, or 100 mg / kg (n = 8).

[0106] For rats raised in the same manner as in Test Example 1, 1 hour after orally administering this compound, inject 0.5 mL of a mixture of three anesthetics corresponding to 100 g of rat body weight into the abdominal cavity of the rats. Attach filter paper of a pre-weighed weight to the palms of the four limbs and tightly wrap with plastic wrap or the like. Absorb the sweat secreted within 30 minutes with the filter paper and recover it.

[0107] (Result)

[0108] The weight of the sweat recovered within 30 minutes is shown in Figure 2 . Even at a concentration of 100 mg / kg, the compound does not affect sweating.

[0109] Example 2: Investigation of the sweating effect of the compound when used in combination with pilocarpine

[0110] The compound was suspended in the MC solution to prepare a dosing solution when in use. The dosing amounts were 0 (MC solution), 10, 30 or 100 mg / kg (n = 8). Additionally, a dosing solution containing pilocarpine hydrochloride was prepared in the same manner as in Test Example 1 when in use.

[0111] One hour after orally administering this compound to rats reared in the same manner as in Test Example 1, 0.5 mL of a mixture of three anesthetics per 100 g of rat body weight was injected into the abdominal cavity of the rats. After recovering the sweat (without pilocarpine) within 30 minutes by the same method as in Example 1, the dosing solution containing pilocarpine hydrochloride was subcutaneously administered (3 mg / kg). Five minutes later, the sweat (containing pilocarpine) secreted within 30 minutes was absorbed with filter paper and recovered. The statistical comparison was performed by paired sample T - test of samples with and without pilocarpine.

[0112] (Results)

[0113] The weights of the sweat recovered from rats with dosing amounts of 0 (MC solution), 10, 30 and 100 mg / kg of this compound are shown in Figure 3 A, Figure 3 B, Figure 3 C and Figure 3 D. At a concentration of 10 mg / kg, no change in the sweating effect according to this compound was observed. On the other hand, at 30 mg / kg and 100 mg / kg, a significant increase in the sweating amount according to this compound was confirmed (*p = 0.032, **p = 0.019). When used in combination with pilocarpine hydrochloride, this compound increased the sweating amount in a dose - dependent manner.

[0114] Example 3: Investigation of the renal excretion rate of the compound

[0115] After 21 days of screening, non - elderly male and female subjects were admitted to the clinical unit one day before administering the compound. On the second day after admission, the subjects were randomly divided into 7 groups of 8 people each. The compound was administered to 6 people in each group, and the corresponding placebo was administered to 2 people. The dosing amounts of the compound were 1, 3, 10, 30, 100, 150 or 200 mg. The subjects were orally administered the compound or placebo once under fasting conditions, and urine was continuously collected for the next 72 hours. Tween (registered trademark) - 20 was added to the collected urine samples, and the urine samples containing 0.5% Tween (registered trademark) - 20 were stored in the dark at - 20 °C until the determination of the parent drug.

[0116] The prototype drug was quantified by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The calibration range measured was from 1.00 to 1000 ng / mL. 20 μL of the internal standard solution (500 ng / mL), 20 μL of orthophosphoric acid, 500 μL of water and 100 μL of the urine sample were mixed, and after solid-phase extraction on an Oasis-MCX μElution 96-well plate (manufactured by Waters Corporation, Japan), it was dissolved in 0.4 mL of the reconstitution solution (50% acetonitrile solution of 25 mmol / L ammonium acetate), and then 1 μL of the solution was injected into the column (Inertsil (registered trademark) ODS-3, 3 μm, 3.0 × 50 mm (manufactured by GL Science)), and quantitative analysis was performed using a Sciex 6500 mass spectrometer (manufactured by Sciex Corporation).

[0117] (Results)

[0118] Table 1 shows the renal excretion rate of the prototype drug in urine. The renal excretion rate of this compound is very low, ranging from 0.875% to 1.64%, indicating that the excretion rate of this compound from the kidney is low.

[0119] [Table 1]

[0120]

[0121] The above embodiments are used to explain the present invention and do not limit the scope of the present invention. That is, the scope of the present invention is represented by the scope of the claims rather than the embodiments. Various modifications made within the scope of the claims and their equivalent meanings are considered to be within the scope of the present invention.

[0122] This application is based on Japanese Patent Application No. 2022-197009 filed on December 9, 2022. The specification, claims and drawings of Japanese Patent Application No. 2022-197009 are incorporated herein by reference in their entirety.

[0123] [Industrial Applicability]

[0124] The present invention can be used in medicine, particularly in body fluid regulators.

Claims

1. A body fluid regulator, comprising a compound represented by formula (I), an ester thereof or a salt thereof, (Chemical formula 1) 2. The humoral regulator according to claim 1, wherein, The body fluid regulator is used in combination with a diuretic in an individual.

3. The humoral regulator according to claim 1, wherein, The body fluid regulator is used in combination with an M3 muscarinic receptor agonist in an individual.

4. The humoral regulator according to claim 1, wherein, The body fluid regulator is used in combination with a thermal stimulus or a thermogenic stimulus in an individual.

5. The body fluid regulator according to any one of claims 2 to 4, wherein The individual suffers from a disease accompanied by excessive body fluid retention.

6. The humoral regulator according to claim 5, wherein, The disease is heart failure, hypertension, cirrhosis, kidney disease, nephrotic syndrome, renal failure, diabetes, drug-induced excessive body fluid retention, lymphedema or lipedema.

7. The humoral regulator according to claim 5, wherein, The disease is renal failure, and the body fluid regulator is used to delay the start time of dialysis therapy.

8. The body fluid regulator according to any one of claims 2 to 4, wherein The individual suffers from a disease accompanied by dry skin or itching.

9. The humoral regulator according to claim 8, wherein, The disease is senile xerosis, atopic dermatitis, psoriasis, ichthyosis, radiation dermatitis, actinic keratosis, senile keratosis, kidney disease, renal failure or diabetes.

10. A body fluid regulating combination, comprising a compound represented by formula (I), an ester thereof or a salt thereof, and a diuretic, (Chemical formula 2) 11. A body fluid regulating combination, comprising a compound represented by formula (I), an ester thereof or a salt thereof, and an M3 muscarinic receptor agonist, (Chemical formula 3) 12. Use of a compound represented by formula (I), an ester thereof or a salt thereof in the preparation of a body fluid regulator, (Chemical formula 4)

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