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Definitions

• the present invention relates to the field of medical technology, and in particular to carboxylic acid compounds and pharmaceutically acceptable salts, prodrugs, and solvates thereof, and methods for their preparation, pharmaceutical compositions comprising the same, and uses thereof.
• Uric acid is the end product of diet and internal metabolism of the body.
• uric acid is mainly present in the blood in the form of sodium urate, and the uric acid value of normal human serum is generally less than 6 mg/dL.
• the sodium urate salt precipitates in the joints and other parts of the body by crystallization, causing gout, urinary stones, kidneys. Diseases such as stones.
• Gout patients are often accompanied by other complications including hypertension, diabetes, hyperlipidemia, abnormal lipid metabolism, atherosclerosis, obesity, metabolic disease, kidney disease, cardiovascular disease and respiratory diseases (Rock, Et.al., Nature Reviews Rheumatology 2013, 9: 13-23).
• the Japanese team Endou reported that the anion transport channel protein URAT1 is the major protein responsible for uric acid reabsorption in the kidney. They also found that there are mutations in the URAT1 gene (which leads to disruption of the protein synthesis, causing non-functional proteins). Blood uric acid is only one-tenth that of normal people (Enomoto et. al., Nature 2002 417: 447-452).
• the main goal of treating gout and its complications caused by elevated blood uric acid is to reduce blood uric acid to less than 6mg/dL.
• the main methods are 1) inhibiting the production of uric acid, such as drugs that inhibit Xanthine oxidase. Allopurinol, febuxostat; 2) inhibition of uric acid reabsorption, such as the inhibition of renal URT1 anion transport channel protein drugs benzbromarone (benzbromarone) and probenecid and is in clinical development In the lesinurad.
• uric acid transport channel proteins in the kidney such as Glut9 and OAT4, which have been found to reabsorb uric acid from the renal tubules back to the blood.
• the kidney is the main route of uric acid excretion (70%), and the intestinal system (through ABCG2, etc.) is responsible for about 30% of uric acid excretion (Sakurai, et.al., Current Opinion in Nephology and Hypertension 2013, 22:545 -550).
• Human urate anion transporter (hURAT1), a member of the anion transporter family, is located on the luminal side of the renal proximal tubular epithelial cells and is mainly involved in the reabsorption of uric acid in renal proximal convoluted tubules. Received. URAT1 accomplishes reabsorption of uric acid and a small amount of secretion by exchange of uric acid in the lumen with uric acid in the lumen. Located in the renal proximal convoluted tubule also has an anion transport channel protein OAT4, which is 42% similar to URAT1 (protein amino acid). Therefore, potent URAT1 inhibitors usually inhibit OAT4 and other anion transport channel proteins.
• OAT4 anion transport channel protein
• thioacetate compounds in the prior art, for example, a class of phenylthioacetate compounds reported in CN102939279A, and a class of thioacetate compounds reported in CN103068801A, wherein sulfur in CN103068801A
• the peracetate compound is essentially obtained by substituting a carbon of a phenyl group in the mother nucleus of the compound of CN102939279A with 1 to 4 N atoms.
• the carboxylic acid compound according to the present invention is represented by the following chemical formula I:
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-6 straight or branched alkylene group, a substituted or unsubstituted C3-6 cycloalkylene group, a substituted or unsubstituted C6-12 arylene group, wherein the substituent a group of -CD 3 , a C1-6 alkyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkylene group or a halogen;
• M is H, Na, K, Ca or C1-4 alkyl
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen, a C1-6 alkyl group or an aromatic ring structure which is bonded to a substituted or unsubstituted C6-10, wherein the substituent in the substituted C6-10 aromatic ring structure Is a halogen, a C1-3 alkyl group or a C1-3 alkoxy group;
• R c is -CN, carboxyl, hydroxy substituted or unsubstituted C 1-6 alkyl, hydroxy substituted or unsubstituted C 3-6 cycloalkyl, hydroxy substituted or unsubstituted, including 1 to 3 selected from O, S and A three- to six-membered heterocycloalkyl group of a hetero atom of N.
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-3 straight or branched alkylene group, a substituted or unsubstituted C3-5 cycloalkylene group, a phenyl group, wherein the substituent is -CD 3 , C1-3 An alkyl group, a cycloalkyl group of C3-5, a cycloalkylene group of C3-5 or a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
• M is H, Na, K, Ca or C1-4 alkyl
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen, a C1-3 alkyl group or are bonded to each other to form a substituted or unsubstituted benzene ring structure, wherein the substituent in the substituted benzene ring structure is a halogen, a C1-3 alkane Or an alkoxy group of C1-3;
• R c is -CN, a carboxyl group, a hydroxy-substituted or unsubstituted C1-3 alkyl group, a hydroxy-substituted or unsubstituted C3-5 cycloalkyl group, a hydroxy group substituted or unsubstituted, and 1 to 3 groups selected from O, S and A ternary to five-membered heterocycloalkyl group of a hetero atom of N.
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-3 straight or branched alkylene group, (cis or trans), (cis or trans), a phenyl group, wherein the substituent is methyl, ethyl, propyl, -CD 3 , a C3-5 cycloalkyl group, a C3-5 cycloalkylene group or a fluorine;
• M is H
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen or are bonded to each other to form a benzene ring;
• R c is -CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxy substituted cyclopropyl, hydroxy substituted cyclobutyl
• X is C or N
• Y, W and Z are each independently C or N;
• A is S
• Q is a substituted or unsubstituted ethylene, propylene, isopropylidene, (cis or trans), (cis or trans), a phenyl group, wherein the substituent is methyl, ethyl, propyl, -CD 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylene, cyclobutylene, cyclopentylene or fluorine;
• M is H
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen or are bonded to each other to form a benzene ring;
• R c is -CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxy substituted cyclopropyl, hydroxy substituted cyclobutyl
• the carboxylic acid compound according to the present invention is represented by the following Chemical Formula II:
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-6 straight or branched alkylene group, a substituted or unsubstituted C3-6 cycloalkylene group, a substituted or unsubstituted C6-12 arylene group, wherein the substituent a group of -CD 3 , a C1-6 alkyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkylene group or a halogen;
• M is H, Na, K, Ca or C1-4 alkyl
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen, a C1-6 alkyl group or an aromatic ring structure which is bonded to a substituted or unsubstituted C6-10, wherein the substituent in the substituted C6-10 aromatic ring structure Is a halogen, a C1-3 alkyl group or a C1-3 alkoxy group;
• R c is -CN, carboxyl, hydroxy substituted or unsubstituted C 1-6 alkyl, hydroxy substituted or unsubstituted C 3-6 cycloalkyl, hydroxy substituted or unsubstituted, including 1 to 3 selected from O, S and A three- to six-membered heterocycloalkyl group of a hetero atom of N.
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-3 straight or branched alkylene group, a substituted or unsubstituted C3-5 cycloalkylene group, a phenyl group, wherein the substituent is -CD 3 , C1-3 An alkyl group, a cycloalkyl group of C3-5, a cycloalkylene group of C3-5 or a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
• M is H, Na, K, Ca or C1-4 alkyl
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen, a C1-3 alkyl group or are bonded to each other to form a substituted or unsubstituted benzene ring structure, wherein the substituent in the substituted benzene ring structure is a halogen, a C1-3 alkane Or an alkoxy group of C1-3;
• R c is -CN, a carboxyl group, a hydroxy-substituted or unsubstituted C1-3 alkyl group, a hydroxy-substituted or unsubstituted C3-5 cycloalkyl group, a hydroxy group substituted or unsubstituted, and 1 to 3 groups selected from O, S and A ternary to five-membered heterocycloalkyl group of a hetero atom of N.
• X is C or N
• Y, W and Z are each independently C or N;
• A is S, N, SO 2 , O or not present
• Q is a substituted or unsubstituted C1-3 straight or branched alkylene group, (cis or trans), (cis or trans), a phenyl group, wherein the substituent is methyl, ethyl, propyl, -CD 3 , a C3-5 cycloalkyl group, a C3-5 cycloalkylene group or a fluorine;
• M is H
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen or are bonded to each other to form a benzene ring;
• R c is -CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxy substituted cyclopropyl, hydroxy substituted cyclobutyl
• X is C or N
• Y, W and Z are each independently C or N;
• A is S
• Q is a substituted or unsubstituted ethylene, propylene, isopropylidene, (cis or trans), (cis or trans), a phenyl group, wherein the substituent is methyl, ethyl, propyl, -CD 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylene, cyclobutylene, cyclopentylene or fluorine;
• M is H
• R 1 , R 2 and R 3 are each independently hydrogen, halogen or absent;
• R a and R b are each independently hydrogen or are bonded to each other to form a benzene ring;
• R c is -CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxy substituted cyclopropyl, hydroxy substituted cyclobutyl
• the carboxylic acid compound according to the invention is selected from the following specific compounds 1 to 41:
• the pharmaceutically acceptable salt of the compound of the present invention is not particularly limited as long as it can be pharmaceutically acceptable, including, but not limited to, ammonium salts, alkali metal salts and alkaline earth metals. Salts such as ammonium salts, sodium salts, potassium salts, calcium salts and the like.
• the invention also includes isotopically-labeled compounds of the invention which are isotopically labeled if one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature.
• the compounds are the same as those described herein.
• isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F and 36 Cl.
• isotopically-labeled compounds of the invention are useful in the identification of compound and/or matrix tissue distribution.
• Deuterated (ie, 3 H) and carbon-14 (ie, 14 C) isotopes are particularly preferred for their ease of preparation and detection.
• substitution with heavier isotopes such as deuterium (ie, 2 H) may provide certain therapeutic benefits resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus may be preferred for use in certain In some situations.
• Isotopically labeled compounds of the invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by procedures similar to those disclosed in the Schemes and/or the Examples below.
• the prodrug of the compound of the present invention is not particularly limited as long as it can be metabolized in the living body to the compound of the invention, and includes, without limitation, an ester or the like, such as a methyl ester, an ethyl ester or the like.
• Step 1 Dissolve the starting reactant 1-1 in dioxane, add potassium acetate, add bis-pinacol borate (B 2 (pin) 2 ), and add palladium catalyst [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, the temperature is raised until the reaction is complete. The reaction solution was cooled, quenched with ice water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and then subjected to EtOAc EtOAc.
• Step 2 Dissolving 3-bromo-4-chloropyridine or 2-bromo-1-chlorobenzene in dimethylformamide and water, and adding the compound (1-2), sodium carbonate and palladium catalyst obtained in the first step at a time. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, followed by a temperature increase reaction. The reaction mixture was cooled, and the mixture was evaporated to ethyl ether.
• Step 3 The compound (1-3) obtained in the step 2 is dissolved in dimethylformamide, sodium sulfide is added, the reaction temperature is raised, the temperature is lowered to room temperature, anhydrous potassium carbonate is added, and the corresponding reactant is added according to the structure of the final product. The temperature is raised and the reaction is continued until the reaction is complete. The reaction mixture was cooled, the reaction was quenched with EtOAc (EtOAc)EtOAc. The crude product is directly invested in the next step.
• EtOAc EtOAc
• Step 4 Compound (1-4) obtained in Step 3, lithium hydroxide, tetrahydrofuran and water were reacted at room temperature overnight. The tetrahydrofuran was removed by concentration, and the aqueous phase was extracted with dichloromethane. The aqueous phase was adjusted to a pH of 4 to 5 with 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane. The organic phase is combined, dried and then dried to give the compound of the formula (1-5).
• Step 1 3-bromopyridin-4-ol or o-bromophenol (3-1) is dissolved in tetrahydrofuran, and sequentially added under nitrogen protection at 0 ° C according to the structure of the final product. Triphenylphosphine and diethyl azodicarboxylate are reacted to room temperature, and the reaction solution is directly concentrated, and the silica gel preparation plate is purified to obtain the compound (3-2).
• Step 2 The obtained compound (3-2), aqueous sodium carbonate solution, compound (1-2), tetrakis(triphenylphosphine)palladium(0) were added to dioxane, and heated to 80 ° C for 12 h. Thereafter, the reaction liquid was cooled to room temperature, and ethyl acetate was added to the reaction mixture, followed by extraction with water and brine. The organic phase is dried, filtered, concentrated, and purified on silica gel to afford compound (3-3).
• Step 3 Compound (3-3), lithium hydroxide or sodium hydroxide is added to tetrahydrofuran/water, and reacted at room temperature for several hours. Thereafter, the pH of the reaction mixture was adjusted with concentrated hydrochloric acid, and ethyl acetate was added to the reaction mixture, and the mixture was washed with water and brine. The organic phase is dried, filtered, concentrated, and purified on silica gel to afford compound (3-4).
• Step 1 Dissolve the starting reactant 4-1 in dioxane, add potassium acetate, add bis-pinacol borate (B 2 (pin) 2 ), and add palladium catalyst [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, the temperature is raised until the reaction is complete. The reaction solution was cooled, quenched with ice water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and then subjected to EtOAc EtOAc EtOAc
• Step 2 Dissolving 3-bromo-4-chloropyridine or 2-bromo-1-chlorobenzene in dimethylformamide and water, and adding the compound (4-2) obtained in the first step, sodium carbonate and palladium catalyst at a time. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, followed by a temperature increase reaction. The reaction mixture was cooled, and the mixture was evaporated to ethyl ether.
• Step 3 The compound (4-3) obtained in the step 2 is dissolved in dimethylformamide, sodium sulfide is added, the reaction temperature is raised, the temperature is lowered to room temperature, anhydrous potassium carbonate is added, and the corresponding reactant is added according to the structure of the final product. The temperature is raised and the reaction is continued until the reaction is complete. The reaction mixture was cooled, and the mixture was evaporated, evaporated, evaporated, evaporated. The crude product is directly invested in the next step.
• Step 4 Compound (4-4) obtained in Step 3, lithium hydroxide, tetrahydrofuran and water were reacted at room temperature overnight. The tetrahydrofuran was removed by concentration, and the aqueous phase was extracted with dichloromethane. The aqueous phase was adjusted to a pH of 4 to 5 with 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane. The organic phase is combined, dried and then dried to give the compound of the formula (4-5).
• Step 1 Dissolve 3-bromo-4-methylpyridine in tetrahydrofuran, add hydrogen diisopropylamide lithium (LDA) after cooling, and then add the corresponding reactant according to the structure of the final product. Continue to react. After the saturated sodium bicarbonate solution was quenched, ethyl acetate was added to the mixture and the mixture was washed with water and brine. The organic phase is dried, filtered, concentrated, and purified on silica gel to afford compound (5-1).
• LDA hydrogen diisopropylamide lithium
• Step 2 Adding compound (5-1), aqueous sodium carbonate solution, compound (1-2), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride to dimethylformamide , heated to the reaction. Ethyl acetate was added to the reaction mixture, and the mixture was extracted with water and brine. The organic phase is dried, filtered, concentrated, and purified on silica gel to afford compound (5-2).
• Step 3 Compound (5-2) and lithium hydroxide were added to tetrahydrofuran/water and reacted at room temperature. The pH of the reaction mixture was adjusted with dilute hydrochloric acid (1M), ethyl acetate was added to the mixture, and the mixture was washed with water and brine. The organic phase is dried, filtered, concentrated, and purified to give compound (5-3).
• Step 1 Compound (1-3), anhydrous potassium carbonate and reactants (or reactant It is added to dimethylformamide, stirred at room temperature, and then stirred at elevated temperature. The mixture was cooled to room temperature, and water and ethyl acetate were evaporated. 2-1).
• Step 2 The compound (6-1-1) and the compound (6-2-1) are respectively dissolved in tetrahydrofuran, and slowly added dropwise to a suspension of sodium hydride in dimethylformamide at 0 ° C, and stirred at 0. A solution of deuterated methyl iodide in dimethylformamide was added dropwise at ° C, and stirred at room temperature overnight. After quenching with water, the pH was adjusted with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give compound (6-1-2) and compound (6-2-2).
• Step 3 Compound (6-1-2) and lithium hydroxide were added to tetrahydrofuran/water (3 mL / 1 mL) and allowed to react at room temperature. The pH of the reaction mixture was adjusted to 4 with dilute hydrochloric acid (1M), ethyl acetate was added to the mixture, and the mixture was washed with brine. The organic phase is dried, filtered, concentrated, and purified to give compound (6-1-3).
• the present invention also provides the use of the carboxylic acid compound, and pharmaceutically acceptable salts, prodrugs and solvates thereof, for the preparation of a urinary excretion drug, preferably targeting URAT1 Urinary acid excretion drugs.
• the present invention provides a method comprising one or more selected from the group consisting of the carboxylic acid compound, and a pharmaceutically acceptable salt, prodrug and solvate thereof, and optionally A pharmaceutical composition of a pharmaceutically acceptable carrier.
• the present invention provides the carboxylic acid compound, and a pharmaceutically acceptable salt, prodrug and solvate thereof, or a pharmaceutical composition thereof, for preparing a tissue for treating or preventing an individual or Use in drugs for diseases caused by abnormal uric acid levels in organs.
• the disease caused by abnormal uric acid level in the tissue or organ of the individual includes: gout, gouty arthritis, recurrent gout attack, hyperuricemia, joint inflammation, arthritis, urolithiasis, kidney disease, kidney stones, kidney Failure, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome, lead poisoning, hyperparathyroidism, psoriasis, and sarcoidosis.
• the disease is hyperuricemia in humans and animals or gout in humans and animals.
• the present invention provides the carboxylic acid compound, and a pharmaceutically acceptable salt, prodrug and solvate thereof, or a pharmaceutical composition thereof, for use in the preparation of blood uric acid for reducing human and animal blood The use of horizontal drugs.
• the carboxylic acid compound and a pharmaceutically acceptable salt, prodrug and solvate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for lowering blood uric acid levels in humans and animals the use of.
• the present invention also provides a combination of the carboxylic acid compound, and a pharmaceutically acceptable salt, prodrug and solvate thereof, or a pharmaceutical composition thereof, and a second agent effective for treating gout.
• the second agent is xanthine oxidase inhibitor, xanthine dehydrogenase inhibitor, xanthine oxidoreductase inhibitor or a combination thereof, preferably allopurinol, febuxostat or a combination thereof.
• the pharmaceutical composition or medicament provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be present in a suitable solid or liquid carrier or diluent. And in a suitable sterilizing device for injection or drip.
• the unit dosage of the formulation comprises 0.05 mg to 200 mg of the compound of formula (I) or (II), preferably, the unit of the formulation
• the dose comprises from 0.1 mg to 100 mg of the compound of formula (I) or (II).
• the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by routes of administration to the mouth, nose, skin, lungs, or the gastrointestinal tract. Most preferably oral.
• the most preferred daily dose is from 0.001 to 10 mg/kg body weight, administered in a single dose, or from 0.001 to 10 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found.
• the term "effective amount” may refer to an effective amount of the dose and period required to achieve the desired effect. This effective amount may vary depending on certain factors, such as the type of disease or condition of the disease at the time of treatment, the configuration of the particular target organ being administered, the size of the individual patient, or the severity of the disease or condition. Those skilled in the art will be able to empirically determine the effective amount of a particular compound without undue experimentation.
• Anti-uric acid activity studies indicate that the compound of the present invention has a good activity of inhibiting uric acid reabsorption, and can be used as a novel and highly effective drug for lowering blood uric acid, especially as a URAT1 inhibitor.
• the starting materials were obtained from commercial sources, such as Alfa Aesar (China) Chemical Co., Ltd., Suiyuan Technology (Shanghai) Co., Ltd., Nanjing Pharmacy Drug Research and Development Co., Ltd., Dalian Lianhua Medical Technology Co., Ltd. Company, Tianjin Fuchen Chemical Reagent Factory, Beijing Jingqi Chemical Products Co., Ltd., Zhangjiagang Amat Chemical Co., Ltd., Sinopharm Chemical Reagent Shaanxi Co., Ltd., etc.
• Step 3 Synthesis of methyl 1-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylate (1-c)
• Step 4 Synthesis of 1-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylic acid (Compound 1)
• the aqueous phase was adjusted to a pH of 4 to 5 with a 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL, 3 times). The organic phase was combined, dried over sodium sulfate and then dried. The compound 1 was obtained as a white solid product.
• Example 1 was followed except that in step 3, the corresponding compound was substituted for methyl 1-(bromomethyl)cyclopropanecarboxylate.
• Compound 3 was synthesized in a similar manner.
• Step 1 Synthesis of methyl 2-(1-(((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate (4-a)
• Step 2 Synthesis of 2-(1-(((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropyl)acetic acid (Compound 4)
• the aqueous phase was adjusted to pH 4 to 5 with 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL, 3 times). The organic phase was combined with sodium sulfate, dried and dried. The product was lyophilized to a white solid.
• Step 2 Synthesis of methyl 2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate (20-c)
• Step 3 Synthesis of 2-(1-((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetic acid (20)
• Step 2 Synthesis of methyl 1-((((methylsulfonyl)oxy)methyl)cyclobutanecarboxylate (17-c)
• Step 3 Synthesis of methyl 1-(((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)methyl)cyclobutanecarboxylate (17-d)
• Step 1 Synthesis of (1-((ethoxycarbonyl)methyl)cyclopropyl)methyl methanesulfonate (11-b)
• Compound 25 was synthesized in a similar manner as in Example 19 except that the corresponding compound was substituted for the aminoacetic acid in the step.
• Compound 26 was synthesized in a similar manner to that in Example 19 except that the corresponding compound was substituted for the aminoacetic acid in the step.
• Compound 27 was synthesized in a similar manner to that in Example 19 except that the corresponding compound was substituted for the aminoacetic acid in the step.
• Step 1 Synthesis of 2-(1-(((3-bromopyridin-4-yl)oxy)methyl)cyclopropyl)acetate (29-a)
• 3-Bromopyridin-4-ol (500 mg, 2.9 mmol) was dissolved in tetrahydrofuran (10 mL) in a 100 mL three-necked flask, and 2-(1-(hydroxymethyl)cyclopropyl) was added sequentially under nitrogen at 0 °C.
• Ethyl acetate (428 mg, 2.9 mmol)
• triphenylphosphine (909 mg, 3.5 mmol
• diethyl azodicarboxylate (609 mg, 3.5 mmol).
• the reaction mixture was directly concentrated, and purified by silica gel chromatography (ethyl acetate / petroleum ether: 2/1).
• Step 2 Synthesis of 2-(1-((3-(4-cyanophenyl)pyridin-4-yl)oxy)methyl)cyclopropyl)acetate (29-b)
• reaction solution was cooled to room temperature, and ethyl acetate (50 ml) was added to the mixture, and the mixture was washed with water (50mL) and brine (50mL).
• the organic phase was dried, filtered, concentrated and purified eluting elut elut
• Step 1 Synthesis of methyl 2-(3-bromopyridin-4-yloxy)-2-methylpropanoate (31-a)
• Methyl 2-(3-bromopyridin-4-yloxy)-2-methylpropanoate (109 mg, 0.4 mmol), aqueous sodium carbonate (0.8 mL, 1.6 mmol, 2M) -Cyanophenylboronic acid (59 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) was added to dioxane (2.4 mL), replaced with nitrogen three times and heated to 80 ° C. 12 hours.
• reaction solution was cooled to room temperature, and the mixture was adjusted to pH ⁇ 4, ethyl acetate (100 ml) was added, and the mixture was washed with water (100 mL) and brine (100 mL). The organic phase is dried, filtered, concentrated and purified by reverse phase to afford white solid.
• Step 2 Synthesis of methyl 2-((3-(4-cyanoisoquinolin-1-yl)pyridin-4-yl)thio)-2-methylpropanoate (10-b)
• Step 3 Synthesis of 2-((3-(4-cyanoisoquinolin-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid (Compound 10)
• the aqueous phase was adjusted to a pH of 4 to 5 with a 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL, 3 times). The organic phase was combined, dried over sodium sulfate and then dried. A crude product was obtained by high pressure crude product.
• reaction solution was poured into 100 mL of ice water and the mixture was evaporated to ethyl ether (150 mL, 3 times) and brine (150 mL, 3 times). The organic phase was dried over anhydrous sodium sulfate and dried.
• Step 2 Synthesis of methyl 2-((3-(3-cyano-1H-indol-1-yl)pyridin-4-yl)thio)-2-methylpropanoate (8-b)
• Step 3 Synthesis of 2-((3-(3-cyano-1H-indol-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid (Compound 8)
• the aqueous phase was adjusted to a pH of 4 to 5 with a 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL, 3 times). The organic phases were combined, dried over sodium sulfate and then evaporated. The crude product was prepared as a pale yellow solid.
• Step 1 Synthesis of methyl 2-(1-((3-bromopyridin-4-ylthio)methyl)cyclopropyl)acetate (22-a)
• reaction solution was cooled to room temperature, and ethyl acetate (100 ml) was added to the mixture, and the mixture was washed with water (100 mL) and brine (100 mL).
• the organic phase was dried, filtered, concentrated and purified eluting elut elut
• Methyl 2-(1-((3-(4-(hydroxymethyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate 140 mg, 0.4
• Methyl hydroxide aqueous solution 0.8 mL, 0.8 mmol, 1 M
• the pH of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid, concentrated, and purified by silica gel chromatography (dichloromethane/methanol: 10/1).
• Step 3 2-(1-(((3-(4-(3-hydroxy)-oxobutan-3-yl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetic acid Synthesis of methyl ester (36-c)
• Step 1 Synthesis of 3-(4-(4-chloropyridin-3-yl)phenyl)oxetan-3-ol (35-a)
• Step 2 Synthesis of 2-((3-(4-(3-hydroxyoxetan-3-yl)phenyl)pyridin-4-yl)thio)-2-methylpropanoic acid (35)
• Step 3 Synthesis of 3-(4-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-4-chloropyridine (34-c)
• Step 4 2-(1-(((3-(4-(4-(4-tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio) Synthesis of Methyl)cyclopropyl)acetate (34-d)
• Step 5 2-(1-(((3-(4-(4-(4-tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio) Synthesis of methyl)cyclopropyl)acetic acid (34-e)
• Step 6 Synthesis of 2-(1-((3-(4-(1-hydroxycyclopropyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetic acid (34) 50mL
• 34-e (0.25 mmol from the previous step)
• tetrabutylammonium fluoride TBAF 0.5 mL, 0.5 mmol, 1 M
• Ethyl acetate 50 mL was added to the mixture and the mixture was washed with water (50mL) and brine (50 ⁇ 3mL).
• the organic phase is dried, filtered, concentrated and purified by reverse phase preparative chromatography to afford white solid.
• Step 1 Synthesis of 4-chloro-3-(4-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)phenyl)pyridine (33-a)
• Step 4 Synthesis of 2-((3-(4-(1-hydroxycyclopropyl)phenyl)pyridin-4-yl)thio)-2-methylpropanoic acid (33)
• Step 2 Synthesis of methyl 2-((5-cyano-[2,3'-bipyridyl]-4'-yl)thio)-2-methylpropanoate (37-b) in a 50 mL single-mouth bottle, 37-a (108 mg, 0.5 mmol), sodium sulfide (117 mg, 1.5 mmol) was dissolved in dimethylformamide (10 mL), and the mixture was warmed to 130 ° C for 1 hour. After cooling, anhydrous potassium carbonate (207 mg, 1.5 mmol) and methyl 2-bromoisobutyrate (272 mg, 1.5 mmol) were added, and the reaction was continued at 130 ° C for 1 hour.
• Step 3 Synthesis of 2-((5-cyano-[2,3'-bipyridyl]-4'-yl)thio)-2-methylpropanoic acid (37)
• Step 1 2-(1-((5-Cyano-[2,3'-bipyridyl]-4'-yl)thio)methyl)cyclopropyl)propanoic acid methyl ester (38-a) synthesis
• Step 2 Synthesis of 2-(1-((5-cyano-[2,3'-bipyridyl]-4'-yl)thio)methyl)cyclopropyl)acetic acid (38)
• Step 1 Synthesis of 4'-(((1-(carboxymethyl)cyclopropyl)methyl)thio)-[2,3'-bipyridyl]-5-carboxylic acid (39)
• Step 1 Synthesis of ethyl 3-(3-bromopyridin-4-yl)propanoate (32-a)
• 3-bromo-4-methylpyridine 500 mg, 2.9 mmol was dissolved in tetrahydrofuran (10 mL) in a 100 mL three-necked flask, and cooled to -78 ° C to add a self-made lithium diisopropylamide LDA ( 3.5 mL, 3.5 mmol), the reaction was carried out for 1 hour, and then ethyl 2-bromoacetate (1.22 g, 7.3 mmol) was added dropwise, and the reaction was continued for 2 hours.
• tetrahydrofuran 10 mL
• a self-made lithium diisopropylamide LDA 3.5 mL, 3.5 mmol
• Step 2 Synthesis of ethyl 3-(3-(4-cyanophthalen-1-yl)pyridin-4-yl)propanoate (32-b)
• Step 2 Synthesis of ethyl 2-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)acetate (40-b)
• Step 3 Synthesis of di-deuterated methyl-2-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)acetic acid (40)
• Step 1 Synthesis of ethyl 2-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)propanoate (41-a)
• Step 2 Synthesis of 2-deuterated methyl-2-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)propanoic acid ethyl ester (41-b)
• Step 3 Synthesis of 2-deuterated methyl-2-((3-(4-cyanophthalen-1-yl)pyridin-4-yl)thio)propanoic acid (41)
• Test Example 1 Evaluation of the biological activity of chemicals inhibiting uric acid absorption using the URAT1 cell model
• the human kidney embryonic cell HEK-293T was grown in a Petri dish containing DMEM and 10% fetal bovine serum nutrient solution (straight 10 cm), and the cells were cultured in an incubator containing 5% carbon dioxide at 37 ° C.
• the plasmid carrying human URAT1 was transfected into HEK-293T cells using TransIT-293 (Mirus Bio LLC). After 72 hours, HEK-293T cells transfected with URAT1 were removed from the incubator and seeded at a density of 60,000 cells per well on a 96-well cell culture plate coated with poly-D-lysine.
• HBSS buffer 100 ⁇ l of ice-cold, chloride-free HBSS buffer was added to gently rinse the cells in the wells to stop the absorption of 14 C-uric acid and rinsed three times in the same manner.
• 150 microliters of cell lysate (100 mM NaOH) was added to each well.
• the cells were plated on a vibrating plate and shaken at 600 rpm for 10 minutes to allow the cells to completely lyse.
• the cell plates were placed in a centrifuge and spun at 1000 rpm for 5 minutes, and 45 microliters of the supernatant was taken from each well and transferred to a 96-well plate (PersoElmer's Isoplate-96 Microplate).
• ⁇ I represents an IC 50 value in the range of 100 nM or less
• ⁇ II represents an IC 50 value in the range of 1000 nM or more to more than 100 nM;

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• 2014
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