Quinoline mercaptoacetate sulfonamide derivatives, intermediates, pharmaceutical derivatives or formulations, and methods for producing and using the same.

Abstract

The present application relates to quinoline mercaptoacetic acid sulfonamide derivatives, intermediates, pharmaceutical derivatives or formulations, as well as methods for preparing and using the same. The structure of the quinoline mercaptoacetic acid sulfonamide derivatives is as shown in the following formula (I). The present application further relates to a method for preparing a compound comprising a structure represented by the following formula: Experiments have revealed that the compounds provided by the present invention have a sufficiently good inhibitory effect on urate transport by URAT1 in HEK293 transfected cells, indicating that such compounds have good prospects for use in the treatment of hyperuricemia and gout. [Formula 1] TIFF2024518849000023.tif47132

Description

[Technical Field]

[0001] This application belongs to the field of pharmaceuticals and relates to the synthesis and use of quinoline mercaptoacetate sulfonamide compounds. This application further relates to the use of these compounds and compositions in the anti-gout field. [Background technology]

[0002] Gout is a metabolic disease in which urate salts are deposited in the joints, cartilage, and kidneys due to elevated blood uric acid levels caused by impaired purine metabolism or decreased uric acid excretion in the body. Its clinical symptoms include recurrent acute and chronic arthritis and soft tissue injuries. Furthermore, hyperuricemia or gout is closely related to the development of diseases such as hypertension, hyperlipidemia, and atherosclerosis.

[0003] The mechanism of gout development involves two stages. In the first stage, uric acid, the final product of purine metabolism in the body, exists as urate under physiological conditions. When its concentration in the blood exceeds the solubility threshold (408 μmol / L or 6.8 mg / dL), it precipitates to form monosodium urate (MSU) crystals, which can be deposited in the joints and surrounding tissues. In the second stage, the irritation of the joints and tissues by the MSU crystals triggers an immune response, leading to spontaneous inflammation. Gout can be described as an inflammatory or immune system pathology caused by a metabolic disease. Clinical symptoms in patients with gout mainly include elevated serum uric acid levels (i.e., hyperuricemia), redness and swelling of the joints, recurrent attacks of acute and chronic arthritis, long-term accumulation and deposition of MSU in and around the joints to form tophi, which in severe cases can cause joint deformities and subsequent damage, as well as renal dysfunction including glomerular and renal tubular lesions, interstitial nephritis, and ultimately renal failure and uric acid kidney stones.

[0004] There are two main approaches to treating gout with drugs. One is to reduce uric acid production in the body using xanthine oxidase inhibitors (XOIS). Xanthine oxidase inhibitors are the oldest antigout drugs, preventing the production of urate salts and hydrogen peroxide through the oxidation of xanthine and hypoxanthine by inhibiting xanthine oxidase. They are still used as first-line drugs to lower uric acid in gout treatment guidelines in many countries, and the main drugs include allopurinol, febuxostat, and topiroxostat. The other approach involves drugs that promote uric acid excretion in the body. This type of drug can promote uric acid excretion by selectively inhibiting organic anion transporters (OATs) expressed in renal proximal tubular cells, such as URAT1 (urate transporter 1) and GLUT9 (glucose transporter 9). This type of drug represents the current main research and development direction for gout treatments, and includes, for example, Verinurad (in clinical trials), which is currently under investigation, as well as drugs already on the market such as probenecid, benzbromarone, and recinurad (launched in the US in 2015).

[0005] Therefore, researching new antigout drugs that are highly efficient, low-toxicity, and have excellent therapeutic effects is of great importance. [Overview of the project]

[0006] The technical solution of this application is as follows: This application aims to incorporate the design, synthesis, and study of reducing blood uric acid activity by targeting the uric acid transporter URAT1 and inhibiting uric acid reabsorption. Based on previous research, structural modifications and improvements were made, and the effect of different groups on the relationship between drug structure and effect was investigated. The in vitro hURAT1 inhibitory activity of the obtained compounds was tested and compared with control products. We hope to discover potentially novel URAT1 inhibitors with superior biological activity.

[0007] This application provides quinoline mercaptoacetate sulfonamide derivatives and methods for producing the same, as well as screening results of the activity of the above compounds as antigout agents and their uses. [Modes for carrying out the invention]

[0008] 1. In its first embodiment, the present invention has a structure represented by the following general formula: [ka] R1 and R2 are each independently selected from hydrogen, halogen, cyano group, nitro group, substituted or unsubstituted C1-C6 linear alkyl group, substituted or unsubstituted C3-C7 cycloalkyl group, substituted or unsubstituted C3-C7 heterocycloalkyl group, or substituted or unsubstituted C4-C12 heterocyclic aryl group, where the heteroatom is selected from one or more of oxygen, sulfur, and nitrogen, and the substituent is selected from one or more of halogen, cyano group, nitro group, alkoxy group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heterocyclic aryl group. The present invention provides a quinoline mercaptoacetate sulfonamide derivative in which R3 and R4 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, or a cycloalkyl group, or in which R3 and R4 constitute a C3-C6 ring.

[0009] In this application, the term "heteroatom" refers to an atom other than a C atom and a H atom within a heterocycloalkyl group and / or a heterocyclic aryl group.

[0010] The inventors of this application have discovered that by using a compound having the structure represented by the above formula I, they can achieve effects equivalent to or better than those of conventional gout drugs. However, to further enhance the therapeutic effect, one or more of the following specific embodiments may be used.

[0011] Regarding R1, In one specific embodiment, R1 is selected from hydrogen, halogen, cyano group, nitro group, C1-C3 linear alkyl group, C1-C4 branched alkyl group, C3-C6 cycloalkyl group, C3-C4 substituted cycloalkyl group, phenyl group, substituted phenyl group, thiophene, and C5-C6 heterocyclic aryl group, where the substituent is selected from halogen, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, and cyclobutyl group, and the heteroatom in the heterocyclic aryl group is selected from one or more of oxygen, sulfur, and nitrogen.

[0012] In one specific embodiment, R1 is selected from hydrogen, halogen, cyano group, nitro group, C1-C3 linear alkyl group, C1-C4 branched alkyl group, and C3-C6 cycloalkyl group.

[0013] In one specific embodiment, R1 is a methyl group, fluorine, bromine, trifluoromethyl, etc.

[0014] Regarding R2, In one specific embodiment, R2 is selected from hydrogen, halogen, cyano group, nitro group, C1-C3 linear alkyl group, C1-C4 branched alkyl group, C3-C6 cycloalkyl group, C3-C4 substituted cycloalkyl group, phenyl group, substituted phenyl group, thiophene, and C5-C6 heterocyclic aryl group, where the substituent is selected from halogen, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, and cyclobutyl group, and the heteroatom in the heterocyclic aryl group is selected from one or more of oxygen, sulfur, and nitrogen.

[0015] In a specific embodiment, R2 is selected from a linear alkyl group of C1-C3, a branched alkyl group of C1-C4, a cycloalkyl group of C3-C6, a substituted cycloalkyl group of C3-C4, a phenyl group, a substituted phenyl group, thiophene, and a heterocyclic aryl group of C5-C6, wherein the substituent is selected from a halogen, a cyano group, a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, and a cyclobutyl group, and the heteroatom in the above heterocycloalkyl group is selected from one or more of oxygen, sulfur, and nitrogen.

[0016] In a specific embodiment, R2 is a methyl group, an ethyl group, thiophene, a cyclopropyl group, etc.

[0017] Regarding the R3 group and the R4 group, In a specific embodiment, R3 and R4 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group of C1-C3, or R3 and R4 form a ring of C2-C4. <0000***89> According to a specific embodiment, R3 and R4 are each independently selected from a hydrogen atom, a methyl group, and an ethyl group.

[0019] According to a specific embodiment, R3 is a methyl group and R4 is a methyl group.

[0020] According to a specific embodiment, one of R3 and R4 is a methyl group and the other is a hydrogen atom.

[0021] The various embodiments of R1, R2, R3, and R4 in the present application may be combined with each other, that is, the present application discloses various combination forms of the various embodiments of R1, R2, R3, and R4. For the sake of brevity of the text, detailed descriptions are omitted. [[ID=***28]]

[0022] Specifically, the compound having the structure represented by the above formula I includes, but is not limited to, the following specific compounds.

[0023] [ka]

[0024] [ka]

[0025] 2. In a second aspect, this application has a structure represented by formula II, [ka] In the compound structure represented by formula II, R1 is R1 in formula I, and Y1 is a methyl group or an ethyl group. The present invention provides intermediates for producing the compound described in the first aspect of this application, wherein R3 and R4 are R3 and R4 in formula I.

[0026] Regarding R1, In one specific embodiment, R1 is selected from hydrogen, halogen, cyano group, nitro group, C1-C3 linear alkyl group, C1-C4 branched alkyl group, C3-C6 cycloalkyl group, C3-C4 substituted cycloalkyl group, phenyl group, substituted phenyl group, thiophene, and C5-C6 heterocyclic aryl group, where the substituent is selected from halogen, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, and cyclobutyl group, and the heteroatom in the heterocyclic aryl group is selected from one or more of oxygen, sulfur, and nitrogen.

[0027] In one specific embodiment, R1 is selected from hydrogen, halogen, cyano group, nitro group, C1-C3 linear alkyl group, C1-C4 branched alkyl group, and C3-C6 cycloalkyl group.

[0028] In one specific embodiment, R1 is a methyl group, fluorine, bromine, trifluoromethyl, etc.

[0029] Regarding R3 and R4 groups, In one specific embodiment, R3 and R4 are independently selected from a hydrogen atom, a C1-C3 alkyl group, or a cycloalkyl group, or R3 and R4 constitute a C2-C4 ring.

[0030] In one specific embodiment, R3 and R4 are independently selected from a hydrogen atom, a methyl group, and an ethyl group.

[0031] In one specific embodiment, R3 is a methyl group and R4 is a methyl group.

[0032] In one specific embodiment, one of R3 and R4 is a methyl group, and the other is a hydrogen atom.

[0033] III. In the third aspect, this application is provided for: Step (1) involves making a first contact between the compound represented by formula III and a sulfide salt in the presence of a first solvent and an inert atmosphere to obtain the compound represented by formula IV. The process includes step (2) of making a second contact between the compound represented by formula IV and the compound represented by formula V in the presence of a first solvent and a carbonate, [ka] In the formula, R1 is R1 in formula I, and Y1 is a methyl group or an ethyl group. R3 and R4 are R3 and R4 in Equation I, The present invention provides a method for producing a compound represented by formula II as described in a second aspect of this application, wherein X is a halogen.

[0034] The first catalytic reaction described above takes place at a temperature of 90-105°C for 1.5-2.5 hours.

[0035] The second catalytic reaction described above takes place at room temperature for 6 to 8 hours.

[0036] The first solvent mentioned above is an organic solvent, and may be, for example, N,N-dimethylformamide or acetonitrile.

[0037] The above-mentioned sulfide salts include, but are not limited to, a combination of one or more of sodium sulfide, potassium sulfide, and magnesium sulfide.

[0038] The carbonates mentioned above include, but are not limited to, a combination of one or more of sodium carbonate, potassium carbonate, and cesium carbonate.

[0039] In one specific embodiment, the method for producing the compound represented by formula II is: Step (1) involves a first catalytic reaction between 4-chloro-6 substituted quinoline and sodium sulfide in the presence of N,N-dimethylformamide (DMF) to obtain 4-mercapto-6 substituted quinoline, The method comprises step (2) carrying out a second contact reaction between the intermediate compound 4-mercapto-6 substituted quinoline and a 2-halogen-fatty acid ethyl ester in the presence of DMF and a carbonate.

[0040] In one specific embodiment, in step (1), the first catalytic reaction is carried out under the protection of an inert gas (e.g., nitrogen gas).

[0041] In one specific embodiment, in step (1), the first contact reaction is carried out at a temperature of 90 to 105°C for a duration of 1.5 to 2.5 hours.

[0042] In one specific embodiment, step (1) uses a mixed solution of ethyl acetate and petroleum ether in a weight ratio of 1:(4-8) as a developing agent for thin-layer chromatography to monitor the reaction.

[0043] In one specific embodiment, the substance obtained by the first contact reaction in step (1) is cooled, extracted, pH adjusted (to 5-6), and solid-liquid separated to obtain the intermediate compound 4-mercapto-6 substituted quinoline.

[0044] In one specific embodiment, in step (2), a mixed solution of ethyl acetate and petroleum ether in a weight ratio of 1:(0.8~1.2) is used as a developing agent for thin-layer chromatography to monitor the reaction.

[0045] In one specific embodiment, the substance obtained by the second contact reaction in step (2) is extracted, washed, dried, concentrated, and separated to obtain the compound represented by II.

[0046] IV. In a fourth aspect, the present application provides a method for producing a compound represented by formula I as described in the first aspect of the present application, comprising the step of sequentially performing a hydrolysis reaction and a sulfonamidation reaction on a compound represented by formula II to obtain a compound represented by formula I.

[0047] In one specific embodiment, the specific reaction equation for producing the compound represented by formula I is as follows: [ka]

[0048] The above hydrolysis reaction can be carried out using methods common in this field.

[0049] In one specific embodiment, the hydrolysis reaction process includes a third contact between a solution containing the compound represented by formula II and an alkaline aqueous solution, followed by heating under reflux.

[0050] In one specific embodiment, the second solvent in the solution containing the compound represented by formula II in the hydrolysis reaction described above is an organic solvent such as methanol or ethanol.

[0051] In one specific embodiment, the alkaline aqueous solution in the hydrolysis reaction described above is a 15-30% by weight NaOH solution.

[0052] In one specific embodiment, after the hydrolysis reaction is complete (determined by TLC monitoring), the mixture is cooled (preferably by simultaneous dilution, for example, by adding cold water) to adjust the pH to an acidic level (e.g., pH = 1 to 2).

[0053] In one specific embodiment, the above hydrolysis reaction involves filtering, washing, and drying the material after pH adjustment to obtain a compound having the structure represented by formula II-2.

[0054] The above sulfonamidation reaction can be carried out by methods common in this field.

[0055] In one specific embodiment, the sulfonamidation reaction process involves a fourth contact reaction between the compound represented by formula II-2 and the sulfonamide compound in the presence of a second solvent (e.g., dichloromethane), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 4-dimethylaminopyridine (DMAP).

[0056] In one specific embodiment, the sulfonamide reaction described above involves first mixing the compound represented by formula II-2 with a second solvent, then adding EDC, DMAP, and the sulfonamide compound at a temperature of -2°C to 5°C, and raising the temperature to room temperature (20°C to 30°C) during the reaction.

[0057] It should be explained that the numerical designations such as "1st," "2nd," "3rd," and "4th" in this application are merely used to distinguish different reaction processes, different forms of existence, or methods of use, and do not indicate any difference in order.

[0058] V. In its fifth aspect, this application provides a pharmaceutically acceptable derivative or formulation of a compound having the structure represented by formula I as described in the first aspect of this application, comprising a pharmaceutically acceptable salt, composition, solvate, hydrate and a pharmaceutically acceptable prodrug.

[0059] VI. In its sixth aspect, the present application provides a pharmaceutically acceptable derivative or formulation of a compound having the structure represented by formula II as described in the second aspect of the present application, comprising a pharmaceutically acceptable salt, composition, solvate, hydrate, and pharmaceutically acceptable prodrug.

[0060] The pharmaceutically acceptable derivatives or formulations described in the fifth and sixth aspects of this application can be obtained by adding one or more pharmaceutically acceptable carriers, auxiliary materials and excipients common in the art and using methods common in the art.

[0061] The pharmaceutically acceptable salts mentioned above include, but are not limited to, Na, K, Li, Mg, Ca, and Zn salts.

[0062] The pharmaceutically acceptable prodrugs described above include, but are not limited to, esters, carbonate esters, enacarbyl esters, thiocarbonates, N-acyl derivatives, N-acyloxy derivatives, and amino acid conjugates.

[0063] The above-mentioned pharmaceutical derivatives or formulations may contain a carrier, which includes, but is not limited to, mannitol, sorbitol, sodium pyrosulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, mercaptoacetic acid, methionine, vitamin C, disodium EDTA, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginates, gelatin, polyvinylpyrrolidone, glycerin, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipid materials, kaolin, talcum powder, calcium stearate, and magnesium stearate. For example, it is used in solid oral formulations.

[0064] The above-mentioned pharmaceutical derivatives or formulations may contain excipients, which include, but are not limited to, adhesives, fillers, diluents, tablet compressors, lubricants, disintegrants, colorants, flavorings, and wetting agents. If necessary, the tablets may be coated. For example, they are used in solid oral formulations.

[0065] The above-mentioned pharmaceutical derivatives or formulations may contain fillers, which include, but are not limited to, cellulose, mannitol, and lactose. For example, they are used in solid oral formulations.

[0066] The above-mentioned pharmaceutical derivatives or formulations may contain disintegrants, which include, but are not limited to, starch derivatives such as starch, polyvinylpyrrolidone, and sodium starch glycolate. For example, they are used in solid oral formulations.

[0067] The above-mentioned pharmaceutical derivatives or formulations may contain a lubricant, which may include, but is not limited to, magnesium stearate. For example, they are used in solid oral formulations.

[0068] The above-mentioned pharmaceutical derivatives or formulations may contain a wetting agent, which may include, but is not limited to, sodium dodecyl sulfate. For example, they are used in solid oral formulations.

[0069] The above-mentioned pharmaceutical derivatives or formulations may include suspensions, which include, but are not limited to, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fat. For example, they may be used in liquid oral formulations (e.g., aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs) or in dry products that can be formulated with water or other suitable carriers before use.

[0070] The above-mentioned pharmaceutical derivatives or formulations may contain emulsifiers, including, but not limited to, lecithin, sorbitan monooleate, and gum arabic. For example, they are used in liquid oral formulations or dried products.

[0071] The above-mentioned pharmaceutical derivatives or formulations may contain a non-aqueous carrier (which may include edible oils), and the non-aqueous carrier includes, but is not limited to, almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol, and ethanol. For example, they are used in liquid oral formulations or dried products.

[0072] The above-mentioned pharmaceutical derivatives or formulations may contain preservatives, including, but not limited to, methylparaben, propyl p-hydroxybenzoate, and sorbic acid. For example, they are used in liquid oral formulations or dried products.

[0073] The above-mentioned pharmaceutical derivatives or formulations, for example, injectable formulations, may contain a sterile carrier. Depending on the carrier and concentration, the compounds of this application may be suspended or dissolved. Solutions are generally prepared by dissolving the compounds in a carrier, filtering and disinfecting before filling into a suitable vial or ampoule, and then filling and sealing. Auxiliary materials such as local anesthetics, preservatives, and buffers may also be dissolved in the carrier. To improve stability, the composition may be frozen after filling into vials and water may be removed under vacuum.

[0074] This application may be for any medicinal dosage form, including tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral solutions, lozenges, granules, granular medicines to be dissolved in hot water and taken, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, hard ointments, creams, sprays, drops, and patches.

[0075] The formulations of this application are preferably in the form of orally administered preparations such as capsules, tablets, oral solutions, granules, pills, powders, elixirs, and ointments.

[0076] The administration route of this application may be oral, non-intestinal, or topical, with oral and injectable administration being preferred. The oral formulation suitable for medicinal use may be a tablet, capsule, granule, or other medicinal liquid formulation such as a solution, emulsion, or suspension. The oral formulation is preferably a tablet, and the tablet may be coated, enterically coated, sustained-release, or quantitatively released. A solid oral formulation may be manufactured by general methods such as mixing, filling, or tableting. By repeated mixing, the active substance can be distributed throughout a composition using a large amount of filler.

[0077] In its seventh embodiment, this application provides for the use of compounds represented by formula I and their pharmaceutically derivatives or formulations, and / or compounds represented by formula II and their pharmaceutically derivatives or formulations, in the manufacture of drugs for adjusting uric acid levels and / or treating indications related to gout.

[0078] The above-mentioned related indications include, but are not limited to, hyperuricemia, gout, gouty arthritis, inflammatory arthritis, nephropathy, nephrolithiasis, arthritis, deposition of urate crystals in the joints, urolithiasis, deposition of urate crystals in the renal parenchyma, gout attacks, nodular gout, or combinations thereof.

[0079] The compounds represented by Formula I or Formula II of this application, and their pharmaceutically derivatives or formulations, possess good URAT1 inhibitory activity and can be used in the treatment of gout and hyperuricemia, offering new pharmaceutical possibilities for the clinical treatment of diseases associated with URAT1 activity abnormalities.

[0080] The endpoints and any values ​​of the ranges disclosed herein should be understood as including values ​​close to them, rather than being limited to those exact ranges or values. For numerical ranges, the intervals between the endpoint values ​​of each range, between the endpoint values ​​of each range and individual point values, and between individual point values ​​can be combined to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. [Examples]

[0081] The present application will be described in detail below with reference to examples. The examples described in this application are only a selection of examples, not all examples. All other examples that a person skilled in the art could obtain without creative work based on the examples in this application are all within the scope of protection of this application.

[0082] The following example will use the manufacturing process of a compound.

[0083] Example 1 The synthesis route for compound 1 is as follows: [ka]

[0084] For the synthesis of intermediate 1-1, 4-chloro-6-methylquinoline (5.0 g, 28 mmol), sodium sulfide (13.5 g, 56 mmol), and 25 mL of DMF were added to a 100 mL three-necked flask and stirred at 100 °C for 2 hours under the protection of nitrogen gas. After cooling to room temperature, the mixture was poured into 100 mL of water and extracted with dichloromethane (50 mL x 3), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid and stirred for 1 hour, after which a yellow solid precipitated. The solution was filtered by suction and vacuum-dried at 50 °C to obtain 4.0 g of yellow solid, with a yield of 81%.

[0085] For the synthesis of intermediates 1-2, intermediate 1-1 (3.3 g, 19 mmol), ethyl bromomethylpropionate (5.5 g, 28 mmol), cesium carbonate (12.3 g, 38 mmol), and 30 mL of DMF were added to a 100 mL three-necked flask and stirred at room temperature for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted with DCM (50 mL x 3) to combine the organic phase. Subsequently, the mixture was washed with saturated brine (100 mL x 2), dried over sodium sulfide, and concentrated the organic phase. Column chromatography (300-400 mesh, eluted with petroleum ether) was performed on the crude product to obtain 5.1 g of a colorless oily substance with a yield of 94%.

[0086] For the synthesis of intermediates 1-3, intermediates 1-2 (5g, 17 mmol), sodium hydroxide (1.38g, 34 mmol), 30 mL of methanol, and 5 mL of water were added to a 100 mL three-necked flask and stirred at 60°C for 2 hours. After the reaction was complete, 20 mL of water was added to dilute the mixture, and the methanol was removed by concentration. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid to obtain a yellow solid, which was then vacuum-dried at 50°C. 3.3 g of crude product was obtained, with a yield of 74%.

[0087] For the synthesis of compound 1, intermediates 1-3 (0.6 g, 2.3 mmol), methylsulfonamide (0.65 g, 6.8 mmol), HATU (1.1 g, 2.9 mmol), DIPEA (0.9 g, 6.9 mmol), and 7 mL of DMF were added to a reaction flask and stirred at room temperature for 24 hours. The reaction mixture was poured into 50 mL of ice water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over sodium sulfide, and concentrated to obtain the crude product. The crude product was prepared under high pressure and separated (reverse-phase C-18 column, mobile phase: acetonitrile and water), concentrated to remove acetonitrile, and then lyophilized to obtain 0.23 g of white solid with a yield of 30%. The mass spectrum was 340.0 (M+H). + ) was.

[0088] Example 2 The synthesis method for compound 2 is the same as that for compound 1, and the synthesis route is as follows. [ka]

[0089] For the synthesis of intermediate 2-1, 4-chloro-6-fluoroquinoline (5.0 g, 28 mmol), sodium sulfide (13.5 g, 56 mmol), and 25 mL of DMF were added to a 100 mL three-necked flask and stirred at 100 °C for 2 hours under the protection of nitrogen gas. After cooling to room temperature, the mixture was poured into 100 mL of water and extracted with dichloromethane (50 mL x 3), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid and stirred for 1 hour, after which a yellow solid precipitated. The solution was filtered by suction and vacuum-dried at 50 °C to obtain 3.8 g of yellow solid, with a yield of 77%.

[0090] For the synthesis of intermediate 2-2, intermediate 2-1 (3.4 g, 19 mmol), ethyl bromomethylpropionate (5.5 g, 28 mmol), cesium carbonate (12.3 g, 38 mmol), and 30 mL of DMF were added to a 100 mL three-necked flask and stirred at room temperature for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted with DCM (50 mL x 3) to combine the organic phase. Subsequently, the mixture was washed with saturated brine (100 mL x 2), dried over sodium sulfide, and concentrated the organic phase. Column chromatography (300-400 mesh, eluted with petroleum ether) was performed on the crude product to obtain 5.2 g of a colorless oily substance with a yield of 93%.

[0091] For the synthesis of intermediate 2-3, intermediate 2-2 (5g, 17 mmol), sodium hydroxide (1.38g, 34 mmol), 30 mL of methanol, and 5 mL of water were added to a 100 mL three-necked flask and stirred at 60°C for 2 hours. After the reaction was complete, 20 mL of water was added to dilute the mixture, and the methanol was removed by concentration. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid to obtain a yellow solid, which was then vacuum-dried at 50°C. 3.1 g of crude product was obtained, with a yield of 69%.

[0092] For the synthesis of compound 2, intermediates 2-3 (0.6 g, 2.3 mmol), methylsulfonamide (0.65 g, 6.8 mmol), HATU (1.1 g, 2.9 mmol), DIPEA (0.9 g, 6.9 mmol), and 7 mL of DMF were added to a reaction flask and stirred at room temperature for 24 hours. The reaction mixture was poured into 50 mL of ice water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over sodium sulfide, and concentrated to obtain the crude product. The crude product was prepared under high pressure and separated (reverse-phase C-18 column, mobile phase: acetonitrile and water), concentrated to remove acetonitrile, and then lyophilized to obtain 0.27 g of white solid with a yield of 35%. The mass spectrum was 343.0 (M+H). + ) was.

[0093] Compound 2 has a mass spectrum of 343,344 (M+H). + ); 1 1H NMR (400MHz, DMSO-d 6 )δ(ppm):8.88(d,J=4.8Hz,1H),8.20~8.10(m,2H),7.90~7.70(m,2H),7.60(d,J=4.8Hz,1H),3.18(s,3H),1.59(s,6H).

[0094] Example 3 The synthesis method for compound 10 is the same as that for compound 1, and the synthesis route is as follows. [ka]

[0095] For the synthesis of intermediate 10-1, 5.0 g of 4-chloro-6-bromo-quinoline, 21 mmol of sodium sulfide, and 25 mL of DMF were added to a 100 mL three-necked flask and stirred at 100 °C for 2 hours under the protection of nitrogen gas. After cooling to room temperature, the mixture was poured into 100 mL of water and extracted with dichloromethane (50 mL x 3), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid and stirred for 1 hour, after which a yellow solid precipitated. The solution was filtered by suction and vacuum-dried at 50 °C to obtain 4.1 g of yellow solid, with a yield of 82%.

[0096] For the synthesis of intermediate 10-2, intermediate 10-1 (4.5 g, 19 mmol), ethyl bromomethylpropionate (4.0 g, 20 mmol), cesium carbonate (12.3 g, 38 mmol), and 30 mL of DMF were added to a 100 mL three-necked flask and stirred at room temperature for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted with DCM (50 mL x 3) to combine the organic phase. Subsequently, the mixture was washed with saturated brine (100 mL x 2), dried over sodium sulfide, and concentrated the organic phase. Column chromatography (300-400 mesh, eluted with petroleum ether) was performed on the crude product to obtain 6.0 g of a colorless oily substance with a yield of 91%.

[0097] For the synthesis of intermediate 10-3, intermediate 10-2 (5 g, 14 mmol), sodium hydroxide (1.38 g, 34 mmol), 30 mL of methanol, and 5 mL of water were added to a 100 mL three-necked flask and stirred at 60°C for 2 hours. After the reaction was complete, 20 mL of water was added to dilute the mixture, and the methanol was removed by concentration. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid to obtain a yellow solid, which was then vacuum-dried at 50°C. 3.3 g of crude product was obtained, with a yield of 72%.

[0098] For the synthesis of compound 10, intermediate 10-3 (0.75 g, 2.3 mmol), methylsulfonamide (0.65 g, 6.8 mmol), HATU (1.1 g, 2.9 mmol), DIPEA (0.9 g, 6.9 mmol), and 7 mL of DMF were added to a reaction flask and stirred at room temperature for 24 hours. The reaction mixture was poured into 50 mL of ice water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over sodium sulfide, and concentrated to obtain the crude product. The crude product was prepared under high pressure and separated (reverse-phase C-18 column, mobile phase: acetonitrile and water), concentrated to remove acetonitrile, and then lyophilized to obtain 0.23 g of white solid with a yield of 25%. The mass spectrum was 417 (M+H). + ) was.

[0099] Compound 10 has a mass spectrum of 417,419 (M+H). +); 1 1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.89 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.10 - 7.90 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 3.40 - 3.30 (m, 2H), 1.62 (s, 6H), 1.14 (t, J = 7.2, 3H).

[0100] Example 4 The synthesis method of Compound 4 is the same as that of 1, and the synthetic route is as follows.

Chemical Structure

[0101] For the synthesis of Intermediate 4-1, 4-chloro-6-trifluoromethylquinoline (5.0 g, 21 mmol), sodium sulfide (10.4 g, 44 mmol), and 25 mL of DMF were added to a 100 mL three-necked flask. Under the protection of nitrogen gas, the mixture was stirred at 100 °C for 2 h. After cooling to room temperature, it was poured into 100 mL of water and extracted with dichloromethane (50 mL × 3). The organic phase was discarded. The aqueous phase was adjusted to pH 5 - 6 with concentrated hydrochloric acid and stirred for 1 h, and a yellow solid precipitated. It was collected by suction filtration and dried under vacuum at 50 °C to obtain 4.5 g of a yellow solid with a yield of 90%.

[0102] For the synthesis of Intermediate 4-2, Intermediate 4-1 (3.3 g, 14 mmol), ethyl bromomethylpropionate (4.0 g, 20 mmol), cesium carbonate (12.3 g, 38 mmol), and 30 mL of DMF were added to a 100 mL three-necked flask and stirred at room temperature for 2 h. The reaction solution was poured into 100 mL of ice water and extracted with DCM (50 mL × 3). The organic phases were combined. Then, it was washed with saturated brine (100 mL × 2), dried with sodium sulfide, and the organic phase was concentrated. Column chromatography (300 - 400 mesh, eluted with petroleum ether) was performed on the crude product to obtain 4.1 g of a colorless oil with a yield of 82%.

[0103] For the synthesis of intermediate 4-3, intermediate 4-2 (4g, 12 mmol), sodium hydroxide (1.38g, 34 mmol), 30 mL of methanol, and 5 mL of water were added to a 100 mL three-necked flask and stirred at 60°C for 2 hours. After the reaction was complete, 20 mL of water was added to dilute the mixture, and the methanol was removed by concentration. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid to obtain a yellow solid, which was then vacuum-dried at 50°C. 2.7 g of crude product was obtained, with a yield of 73%.

[0104] For the synthesis of compound 4, intermediate 4-3 (0.72 g, 2.3 mmol), methylsulfonamide (0.65 g, 6.8 mmol), HATU (1.1 g, 2.9 mmol), DIPEA (0.9 g, 6.9 mmol), and 7 mL of DMF were added to a reaction flask and stirred at room temperature for 24 hours. The reaction mixture was poured into 50 mL of ice water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over sodium sulfide, and concentrated to obtain the crude product. The crude product was prepared under high pressure and separated (reverse-phase C-18 column, mobile phase: acetonitrile and water), concentrated to remove acetonitrile, and then lyophilized to obtain 0.77 g of white solid with a yield of 86%. The mass spectrum was 393 (M+H). + ) was.

[0105] Compound 4 has a mass spectrum of 393,395 (M+H). + ); 1 H NMR(400MHz,CDCl3)δ(ppm):8.91(d,J=5.2Hz,1H),8.55(s,1H),8.33(d,J=8.8Hz,1H), 8.00 (dd, J=8.8Hz, J=1.6Hz, 1H), 7.45 (d, J=5.2Hz, 1H), 3.31 (s, 3H), 1.78 (s, 6H).

[0106] Example 5 The synthesis method for compound 18 is partially the same as that for compound 10, and the synthesis route is as follows. [ka]

[0107] For the synthesis of compound 18, intermediate 10-3 (0.75 g, 2.3 mmol), thiophenesulfonamide (1.1 g, 6.8 mmol), HATU (1.1 g, 2.9 mmol), DIPEA (0.9 g, 6.9 mmol), and 7 mL of DMF were added to a reaction flask and stirred at room temperature for 24 hours. The reaction mixture was poured into 50 mL of ice water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over sodium sulfide, and concentrated to obtain the crude product. The crude product was prepared under high pressure and separated (reverse-phase C-18 column, mobile phase: acetonitrile and water), concentrated to remove acetonitrile, and then lyophilized to obtain 0.34 g of white solid with a yield of 32%. The mass spectrum was 471 (M+H). + ) was.

[0108] Compound 18 has a mass spectrum of 471 (M+H). + ); 1 1H NMR (400MHz, DMSO-d 6 )δ(ppm):8.57(d,J=4.8Hz,1H),8.50(d,J=2.0Hz,1H),8.05(dd,J=4.8Hz,J=2.0Hz,1H),7.98(s,1H),7.96(d,J=2.0 Hz, 1H), 7.77 (dd, J=4.0Hz, J=1.6Hz, 1H), 7.22 (dd, J=4.8Hz, J=4.0Hz, 1H), 6.87 (d, J=4.8Hz, 1H), 1.54 (s, 6H).

[0109] Activity testing of target compounds 1. Purpose of the experiment The in vitro inhibitory activity (IC50) of the compound against hURAT1 will be tested.

[0110] 2. Experimental materials 2.1 The test compounds are as follows: [ka]

[0111] 2.2 The HEK-293T cell line, which stably expresses hURAT, was independently constructed by Eizhi Chemical Research Co., Ltd.

[0112] 2.3 The following materials were purchased by Eizhi Chemical Research Co., Ltd. [Table 1]

[0113] III. Experimental Method 3.1 Preparation of experimental reagents [Table 2]

[0114] 3.2 Cell culture and inoculation (1) HEK-293T cell line that stably expresses hURAT1 was cultured, and the culture medium composition was DMEM medium + 10% fetal bovine serum + 500 μg / ml G418 + 1% P / S.

[0115] (2) Once the cells had grown to 80%, the culture medium was discarded, the cells were washed once with PBS, then pancreatin-EDTA was added to digest them, and once the cells had detached from the cell wall, the culture medium was added and the cells were blown off, the cells were collected by centrifugation, the culture medium was added and blown to form a cell suspension.

[0116] (3) Cell density 7 × 10 5 After adjusting to / ml, the cells were inoculated at a volume of 100 μL / well into 96-well cell culture plates with white walls and a clear bottom, and cultured for 12-24 hours.

[0117] 3.3 Compound Preparation (1) The compound was prepared as a mother liquor with DMSO at a concentration of 20 mM, and then diluted with DMSO to a concentration of 1 mM and added to 96 wells.

[0118] (2) Each quality control compound was separately placed in a 96-well plate to form a 100× compound plate.

[0119] (3) The corresponding wells in another 96-well plate were diluted 50-fold with Cl-free HBSS buffer to create a 2× compound plate (plate 2).

[0120] (4) Then, put 0.1 μCi / ml into a new 96-well plate. 14 Add 30 μL / well of buffer containing C-uric acid, and then add 30 μL / well of the 2× diluted compound to prepare the plate for use as a 1× compound plate (plate 1).

[0121] 3.4 In cells that stably express hURAT1 14 Absorption of C-uric acid (1) After the cells in the 96-well plate have been cultured to adhere to the wall, an absorption test can be performed.

[0122] (2) The cells were washed once with 200 μL / well of preheated buffer.

[0123] (3) Immediately after suction drying each well, the corresponding compound and 0.1 μCi / ml 14 A solution containing C-uric acid was added at a rate of 50 μL / well.

[0124] (4) The plates containing the compound were incubated in a 37°C incubator for 5 minutes.

[0125] (5) Immediately add 150 μL of cold buffer to each well to stop absorption. Wash each well three times with buffer. (Note: Avoid cell loss as much as possible during washing).

[0126] (6) Add 50 μL / well of lysate to each well, place the well on a shaker, and shake at a speed of 900 rpm for 5 minutes.

[0127] (7) Add 150 μL / well of the scintillation solution Microsint40 to each well and shake at a speed of 900 rpm for 5 minutes.

[0128] (8) Finally, the microplate was transferred to a MicroBeta2 instrument (manufactured by Perkin Elmer) and its radioactivity was measured.

[0129] (9) The data was analyzed and the IC50 of each compound was calculated using GraphPad Prism 5 software.

[0130] IV. Experimental Results The experimental results are shown in Table 1. Activity tests indicated that compounds A to E, among others, exhibited good inhibitory activity and are worth further investigation.

[0131] [Table 3]

[0132] The embodiments described above are for illustrative purposes only and do not limit the embodiments of this application. Those skilled in the art can make other different forms of changes and variations based on the above description. It is not possible to exhaustively list all embodiments here. All obvious changes or variations derived from the technical solutions of this application are still covered by this application.

Claims

1. A quinoline mercaptoacetate sulfonamide derivative represented by the following formula. 【Chemistry 1】

2. A method for producing the quinoline mercaptoacetate sulfonamide derivative described in Claim 1, comprising the step of sequentially performing a hydrolysis reaction and a sulfonamidation reaction on a compound represented by the following formula II to obtain the compound described in Claim 1. 【Chemistry 2】 In formula II, R1 is trifluoromethyl, R3 and R4 are methyl, and Y1 is methyl or ethyl.

3. The method according to claim 2, wherein the hydrolysis reaction process includes contacting a solution containing the compound represented by formula II with an alkaline aqueous solution and heating under reflux to obtain the compound represented by formula II-2 below. 【Transformation 3】 In formula II-2, R1 is trifluoromethyl, and R3 and R4 are methyl.

4. The method according to claim 3, wherein the sulfonamidate reaction step includes contacting the compound represented by formula II-2 with a sulfonamide compound in the presence of a solvent.

5. The method according to any one of claims 2 to 4, comprising the following reaction. 【Chemistry 4】 In the formula, R1 is trifluoromethyl, R2 is methyl, R3 and R4 are methyl, and Y1 is methyl or ethyl.

6. A pharmaceutical formulation of a quinoline mercaptoacetate sulfonamide derivative according to Claim 1, wherein the pharmaceutical formulation comprises a pharmaceutically acceptable salt and the quinoline mercaptoacetate sulfonamide derivative according to Claim 1.

7. Use of the quinoline mercaptoacetate sulfonamide derivative according to Claim 1 and the pharmaceutical preparation according to Claim 6 in the manufacture of a drug for adjusting uric acid levels and / or treating indications related to gout.

8. The use according to claim 7, wherein the aforementioned related indications include hyperuricemia, gout, gouty arthritis, inflammatory arthritis, nephropathy, nephrolithiasis, arthritis, deposition of urate crystals in the joints, urolithiasis, deposition of urate crystals in the renal parenchyma, gout attacks, nodular gout, or a combination thereof.

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