WO2017173965A1 - Nouvel inhibiteur urat1 et son application pharmaceutique - Google Patents

Nouvel inhibiteur urat1 et son application pharmaceutique Download PDF

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WO2017173965A1
WO2017173965A1 PCT/CN2017/079251 CN2017079251W WO2017173965A1 WO 2017173965 A1 WO2017173965 A1 WO 2017173965A1 CN 2017079251 W CN2017079251 W CN 2017079251W WO 2017173965 A1 WO2017173965 A1 WO 2017173965A1
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pyridin
indolyl
imidazo
methyl
acid
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PCT/CN2017/079251
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English (en)
Chinese (zh)
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史东方
傅长金
承曦
朱江华
顾杰
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江苏新元素医药科技有限公司
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Priority to CN201780001004.3A priority Critical patent/CN107683282B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds for the treatment of disorders associated with abnormal levels of uric acid and pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions containing the same, and their use as URAT1 inhibitors for the treatment of gout, for the treatment of hyperuricemia and Reduce serum uric acid and other uses.
  • Gout is a group of heterogeneous and metabolic diseases caused by long-term metabolic disorders and/or decreased uric acid excretion in the human body. It is divided into primary and secondary. Clinical manifestations of hyperuricemia and urate crystal deposition, leading to recurrent arthritis, gouty nephropathy, gout condensate deposition, urinary acid urinary system coagulation production, etc. (Pharmaceutical Herald. 2006, 25 (8 ): 803-806). Hyperuricemia is a serum uric acid content exceeding normal, generally more than 417 ⁇ mol / L (7.0 mg / dL) for men and 357 ⁇ mol / L (6.0 mg / dL) for women.
  • gout and hyperuricemia are not only affected by age, gender, region, ethnicity, heredity, environment, etc., but also with other metabolic syndromes such as obesity, hypertension, hyperlipidemia, coronary heart disease, insulin resistance and Diabetes is closely related (Circ J 2005, 69(8): 928-933.; Metabolism. 2008, 57(1) 71-76.; Curr Opin Rheumatol. 2005, 17(3): 341-345.). Studies have shown that hyperuricemia and hypertension are the main causes of metabolic syndrome, and there are mechanisms of interaction that can exacerbate the risk factor for cardiovascular disease (Korean J Gastroenterol, 2008, 49(3): 173-176.).
  • uric acid in the kidney can directly regulate the level of blood uric acid, and about 85% of gout is caused by reduced uric acid excretion (Curr Opin Nephrol Hypertens, 2009, 18(5): 428-432.).
  • Physiological and pharmacological studies define the classic mode of renal uric acid transport: glomerular filtration, renal tubular reabsorption, renal tubular secretion, post-secretion reabsorption, especially tubular reabsorption, which affects uric acid excretion. The most important factor.
  • UAT urate unidirectional transporters
  • OAT1 and OAT3 urate anion transporters
  • URAT1 is responsible for the transport of uric acid into the epithelial cells through the brushy edge of the proximal convoluted tubule. It is the main uric acid reabsorption transport protein in the human body, and is specifically expressed in the proximal convoluted epithelial cells, independent of membrane voltage and intracellular and extracellular pH. The effect of the value is an electrically neutral urate exchanger, which is time-dependent and saturated (Nature. 2002, 417 (6887): 447-452.).
  • URAT1 (Arthritis And Rheumatism, 1975, 18(6): 805-809.).
  • URAT1 is a member of the organic anion transporter (OAT) superfamily. It is encoded by the SLC22A12 gene and consists of 9 exons with 9 exons. It has 12 transmembrane domains with a full-length cDNA of 2642 bp and a coding region of 1659 bp. There are a variety of mutations that are prone to abnormal uric acid metabolism. A meta-analysis indicates that the SLC22A12 gene contributes 0.13% to the blood uric acid level.
  • the uric acid excretion drugs currently used in the market for the treatment of gout are Benzbromarone, Probenecid, Sulfinpyrazone, Lesinurad and the like.
  • Benzobromarone is currently the most commonly used drug for the treatment of hyperuricemia and gout. It mainly acts as a uric acid excretion by inhibiting the reabsorption of uric acid by URAT1.
  • probenecid and sulfinpyrazone have a poor effect on uric acid excretion in the treatment of gout.
  • Benzobromarone is a benzofuran derivative developed in the 1960s by the French company Snaofi-Synthelabo, in 1976 listed in Germany in the past, it has been widely used in the treatment of gout and hyperuricemia.
  • benzbromarone has serious side effects such as liver damage.
  • the drug may cause the risk of fulminant hepatitis in 2003, it has been withdrawn from the market in some countries (Pharmaceutical Herald, 2006, 25(8): 803).
  • Lesinurad is an oral solid preparation that can be combined with xanthine oxidase inhibitors for the treatment of gout-related hyperuricemia.
  • Lesinurad when it is combined with xanthine oxidase inhibitors, headache, flu, increased serum creatinine and gastroesophageal reflux disease; when there is often a renal function-related adverse reaction at a dose of 400 mg, it can also cause serious Cardiovascular adverse reactions.
  • Lesinurad is a moderate inhibitor of the P450 enzyme CYP2C9 and a sensitive CYP3A substrate, which is not recommended for patients with severe liver injury.
  • RDEA-3170 currently developed by AstraZeneca, has been in clinical phase II, and some of the disclosed URAT1 inhibitor patents include WO2005121112, WO2011159839, WO2007086504, WO2008062740, WO2009070740, WO2011085009, WO2014017643, WO2014183555, WO2014077285, and the like.
  • the present invention provides a novel structural URAT1 inhibitor and finds that such compounds have good URAT1 inhibitory activity, and it is expected that the novel URAT1 inhibitor can be used for the treatment of gout, hyperuricemia and related renal diseases, and lowering blood uric acid concentration.
  • Another object of the present invention is to provide a pharmaceutical use of the above URAT1 inhibitor.
  • the object of the invention can be achieved by the following measures:
  • Y or Z are independently N or CH
  • R 1 or R 2 are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C 1-4 alkyl, substituted C 1-4 alkyl, C 3-4 cycloalkyl, C 1- 4 alkoxy, substituted C 1-4 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl are one or more of which substituents
  • the group is selected from the group consisting of halogen, cyano, hydroxy, amino, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy or C 1-2 haloalkoxy,
  • R 3 or R 4 are each independently selected from H or C 1-3 alkyl, or R 3 and R 4 together form a 3-6 membered cycloalkyl group,
  • R 5 is H, C 1-4 alkyl or substituted C 1-4 alkyl, the substituent of which is selected from C 1-2 alkoxy, hydroxy or amino.
  • the compound is selected from the group consisting of a compound of formula (II), formula (III) or formula (IV),
  • R 1 or R 2 are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, substituted C 1-3 alkane. , C 3-4 cycloalkyl, C 1-3 alkoxy, substituted C 1-3 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl, substituted thiophene
  • R 1 or R 2 are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy, phenyl, halophenyl, cyanophenyl, methylphenyl, ethylphenyl, methoxyphenyl, One or more of an ethoxyphenyl group, a naphthyl group, and a cyanophenyl group.
  • R 3 or R 4 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, or R 3 and R 4 are taken together to form 3- 5-membered cycloalkyl.
  • R 5 is H or C 1-3 alkyl.
  • each compound of the invention may be selected from:
  • the present invention also provides a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer and a mixture thereof. And methods of pharmaceutically acceptable salts thereof, the method comprising:
  • the compound of the formula (IA) is subjected to a substitution reaction with a compound of the formula (IB), optionally further subjected to a hydrolysis reaction under basic conditions to obtain a compound of the formula (I); wherein: X 1 is a leaving group or SH, The leaving group is halogen, OMs (methanesulfonyloxy), OTs (p-toluenesulfonyloxy) or OTf (trifluoromethanesulfonyloxy), preferably halogen; X 2 is halogen, OMs, OTs or SH; when X 1 is a leaving group, X 2 is SH; when X 1 is SH, X 2 is halogen, OMs, OTs.
  • Other groups are defined as defined in the claims and the general formula (I).
  • alkyl is used to mean a saturated hydrocarbon group
  • C 1-4 alkyl means a saturated hydrocarbon group having 1 to 4 carbon atoms, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl and neobutyl.
  • alkyl is preferably C 1-4 alkyl, more preferably C 1-3 alkyl.
  • the substituted alkyl group means an alkyl group having one or more substituents. When the number of the substituents is two or more (including two), the respective substituents may be the same or different.
  • the substituted C 1-4 alkyl group means a saturated hydrocarbon group having 1 to 4 carbon atoms having one or more (2 or more) substituents; for example, "fluoromethyl” means having one or two The methyl group of one or three fluorine substituents, "fluoroethyl” means an ethyl group having 1 to 5 fluorine substituents.
  • Cycloalkyl means a monocyclic or fused ring that is all carbon (a “fused” ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one of which Or a plurality of rings do not have a fully connected ⁇ -electron system, examples of cycloalkyl groups (not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene , cycloheptane and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted.
  • the substituent is preferably one or more groups each selected from the group consisting of alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, fluorenyl, Alkyl, aryl, cyano, halogen, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamoyl, N-carbamoyl, C-amido, N-amido, nitro, Amino and -NR 10 R 11 , wherein R 10 and R 11 are as defined above.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated ⁇ -electron system.
  • unsubstituted heteroaryl sites are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, indole, tetrazole, triazine and carbazole.
  • Heteroaryl groups can be substituted or unsubstituted.
  • the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from the group consisting of lower alkyl, three Haloalkyl, halogen, hydroxy, lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarba Acyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino, R 10 S(O)-, R 10 S(O) 2 ⁇ , ⁇ C(O)OR 10 , R 10 C(O)O ⁇ and ⁇ NR 10 R 11 , wherein R 10 and R 11 are as defined above.
  • Preferred heteroaryl groups are optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, N-amido, mono or dioxane Amino group, carboxyl group or N-sulfonylamino group.
  • Halo C 1-4 alkyl means a saturated hydrocarbon group having from 1 to 4 carbon atoms having one or more (ie two or more) halogen substituents, wherein each halogen substituent may be the same, Can be different.
  • fluoro C 1-3 alkoxy group means a saturated hydrocarbon group having 1 to 3 carbon atoms having one or more (ie, 2 or more) fluorine substituents.
  • the halogenated C 1-4 alkyl group in the present invention includes, but is not limited to, a halogenated methyl group, a halogenated ethyl group, a halogenated n-propyl group, a halogenated isopropyl group, a halogenated n-butyl group, a halogenated isobutyl group, Halogenated neobutyl, etc., more specific groups include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, tetrafluoroethyl , trifluoroethyl, difluoroethyl, monofluoroethyl, trichloroethyl, dichloroethyl, monochloroethyl, and the like.
  • Halogen includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • Alkoxy means an "-O-alkyl” group having from 1 to 10 carbon atoms.
  • the C 1-4 alkoxy group means that the alkoxy group has 1 to 4 carbon atoms.
  • the alkoxy group in the invention is preferably a C 1-4 alkoxy group, more preferably a C 1-3 alkoxy group.
  • the substituted alkoxy group means an alkoxy group having one or more substituents. When the number of the substituents is two or more (including two), the respective substituents may be the same or different.
  • the substituted C 1-4 alkoxy group means an alkoxy group having 1 to 4 carbon atoms having one or more (ie, 2 or more) substituents.
  • Alkoxy groups in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and neobutoxy.
  • Cyano refers to the -CN group.
  • Carboxy refers to a -COOH group.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid And perchloric acid, etc., organic acids
  • organic acids for example (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, neighbors Phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, supplemented with a pharmaceutically acceptable adjuvant.
  • Each compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the preparation of a uric acid excretion drug, particularly for the preparation of a medicament for treating or preventing hyperuricemia or gout.
  • Figure 1 is a graph showing the growth inhibitory effect of Compound 6 and Lesinurad on human hepatoma cell HepG2.
  • Step C A solution of bromine (4.31 g, 27.0 mmol) in dichloromethane (10 mL) was added dropwise to 2-amino-6-(trifluoromethyl)pyridine (4.37 g, 27.0 mmol). In a solution of methyl chloride (70 mL), the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate (40 mL) was added and the mixture was evaporated. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc.
  • Step D A mixture containing Compound 3 (2.77 g, 11.5 mmol), 40% aqueous chloroacetaldehyde (6.77 g, 34.5 mmol), sodium bicarbonate (966 mg, 11.5 mmol) and ethanol (25 mL) was sealed at 110 ° C The tube was stirred overnight. After slightly cooling, a 40% aqueous solution of chloroacetaldehyde (6.77 g, 34.5 mmol) and sodium hydrogencarbonate (966 mg, 11.5 mmol) were added, and stirring was continued at 110 ° C overnight. After cooling, most of the solvent was evaporated under reduced pressure.
  • Step E Dioxane (6 mL), Compound 4 (100 mg, 0.377 mmol), Pd 2 (dba) 3 (17.3 mg, 0.019 mmol) and 4,5-bisdiphenylphosphine were sequentially added to a three-necked flask A. -9,9-Dimethoxyxanthracene (xantphos) (22 mg, 0.0380 mmol), and the mixture was stirred under nitrogen for 40 min. To another three-necked flask B was added dioxane (4 mL), compound 2 (100 mg, 0.745 mmol) and diisopropylethylamine (98 mg, 0.758 mmol), and the mixture was stirred under nitrogen for 20 min.
  • Step F A mixture containing compound 5 (54 mg, 0.170 mmol), THF (1 mL), methanol (2mL), water (2mL) and sodium hydroxide (21mg, 0.525mmol) was stirred overnight at room temperature. Water (10 mL) was added, washed with methyl t-butyl ether (MTBE) (10 mL ⁇ 2), and the aqueous phase was collected.
  • MTBE methyl t-butyl ether
  • Step A A solution of bromine (5.25 g, 32.9 mmol) in dichloromethane (10 mL) was added dropwise to a solution of methyl 6-aminopicolinate (5.0 g, 32.9 mmol) in dichloromethane (70 mL). The resulting mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate (40 mL) was added and the mixture was evaporated. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc.
  • Step B Compound 11 (1.83 g, 7.92 mmol), 40% aqueous chloroacetaldehyde (4.76 g, 23.7 mmol), dioxane (16 mL), sodium bicarbonate (670 mg, 7.98 mmol) and water (4 mL) The mixture was stirred at 90 ° C overnight. After slightly cooling, a 40% aqueous solution of chloroacetaldehyde (2.38 g, 12.1 mmol) was added, and then the mixture was stirred at 90 ° C and stirring was continued overnight. After cooling, most of the solvent was evaporated under reduced pressure. Water (20 mL) was added and the pH was adjusted to 7-8 with saturated sodium hydrogen carbonate.
  • Step C A mixture containing compound 12 (100 mg, 0.392 mmol), sodium sulphate sulphate (122 mg, 0.508 mmol) and DMF (4 mL) was stirred at 70 ° C for 1 hour, and after cooling slightly, methyl bromoisobutyrate was added ( 284 mg, 1.57 mmol) and potassium carbonate (81 mg, 0.587 mmol), and the mixture was stirred at 60 ° C overnight. After the addition of water (20 mL), EtOAc (EtOAc m.
  • Step D Compound 13 (32 mg, 0.14 mmol) was dissolved in THF (1 mL) and methanol (2mL), and 2M sodium hydroxide solution (3mL) was added, and the mixture was stirred at 40 ° C for 1 hour. About half of the solvent was distilled off under reduced pressure at 40 ° C, water (20 mL) was added, and washed with MTBE (10 mL ⁇ 2), and the aqueous phase was collected. The aqueous phase was adjusted to pH 5 to 6 with dilute aqueous hydrochloric acid, and the solvent was evaporated under reduced pressure.
  • Step A A mixture containing 2-amino-6-fluoropyridine (500 mg, 4.46 mmol), bromoacetone (1.83 g, 13.4 mmol), ethanol (10 mL) and sodium bicarbonate (375 mg, 4.46 mmol) was sealed at 90 ° C The tube was stirred overnight. After cooling, most of the solvent was distilled off under reduced pressure, and an appropriate amount of water was added, and the pH was adjusted to 7 to 8 with a saturated sodium hydrogen carbonate solution. It was extracted with ethyl acetate (20 mL ⁇ 3) and dried over anhydrous sodium sulfate.
  • Step C Compound 24 is hydrolyzed according to the procedure of Example D in Example 3, and acidified to give 2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indenyl] Propionic acid (25).
  • Step B 2.0 M bistrimethylsilylamino sodium THF solution (16 mL, 32 mmol) was added dropwise to a solution of compound 26 (3.4 g, 17.9 mmol) in THF (15 mL) at -30 to -40 °C. Stirring was continued for 1 hour after the addition. Then, a solution of iodine (5.4 g, 21.3 mmol) in THF (10 mL) was added dropwise at this temperature, and stirring was continued for 40 minutes.
  • Step A A mixture containing compound 3 (300 mg, 1.24 mmol), isopropanol (4 mL) and N,N-dimethylformamide dimethyl acetal (DMFDMA) (195 mg, 1.64 mmol) was refluxed under nitrogen. Stir for 3 hours. After cooling to 50 ° C, hydroxylamine hydrochloride (114 mg, 1.64 mmol) was added, and the resulting mixture was stirred at this temperature for 6 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc) The solvent was evaporated under reduced pressure and the product was purified mjjjjjjjjj 2-yl]-N'-hydroxyformamidine (30) (300 mg). The yield was 84.9%.
  • Step B The compound 30 (290 mg, 1.02 mmol), THF (10 mL) and polyphosphoric acid (700 mg, 2.07 mmol) was stirred at 100 ° C overnight, and most of the solvent was evaporated under reduced pressure. After adding an appropriate amount of water, the pH was adjusted to 8 to 9 with a 2M sodium hydroxide solution, and then extracted with ethyl acetate (15 mL ⁇ 2) and dried over anhydrous sodium sulfate.
  • Step A To a mixture containing compound 4 (500 mg, 1.89 mmol), lithium chloride (80 mg, 1.89 mmol), NCS (265 mg, 1.98 mmol) and DMF (10 mL) was added perchloric acid (5 drops). Stir at room temperature for 3 hours. Water (40 mL) was added, and the mixture was evaporated. The solvent was evaporated under reduced pressure and the product was purified mjjjjjjjjjjjjj Imidazo[1,2-a]pyridine (49) (280 mg). The yield was 49.5%.
  • Step A To a solution containing 2-amino-6-bromopyridine (3.46 g, 20 mmol), 4-cyanobenzeneboronic acid (3.7 g, 25.2 mmol), potassium phosphate trihydrate (16.6 g, 62.3 mmol), water (20 mL) Tricyclohexylphosphine (560 mg, 2.0 mmol) and palladium acetate (224 mg, 1.0 mmol) were added to a mixture of toluene (80 mL).
  • steps B, C(C1), D(D1), and E(D1) are sequentially referred to steps C, D, and E in Example 1.
  • F 2- ⁇ [5-(4-cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl ⁇ -2-methylpropanoic acid (57) and 2- ⁇ [5 -(4-Cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indolyl ⁇ -2-methylpropanoic acid (60).
  • Example 16 2- ⁇ [8-(4-Cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl ⁇ -2-methylpropionic acid (66) and 2 Synthesis of - ⁇ [6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]fluorenyl ⁇ -2-methylpropionic acid (69)
  • Step C Compound 62 (200 mg, 0.655 mmol), (4-cyanonaphthalen-1-yl)boronic acid (142 mg, 0.721 mmol), n-butanol (15 mL), sodium carbonate (138 mg, 1.30 mmol) and A mixture of (triphenylphosphine)palladium (40 mg, 0.0346 mmol) was stirred under reflux overnight under nitrogen. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc.
  • Step E A mixture containing compound 65 (70 mg, 0.170 mmol), THF (1.5 mL) and methanol (l. Water (10 mL) was added, extracted with MTBE (10 mL ⁇ 2), and the aqueous phase was collected. The aqueous phase was adjusted to pH 3-4 with 2M hydrochloric acid, then extracted with ethyl acetate (15 mL ⁇ 2) and dried over anhydrous sodium sulfate.
  • steps C1, D1 and E1 are respectively referred to steps C, D and E in this example to obtain 2- ⁇ [6-cyanophthalen-1-yl)imidazo[1,2-a]pyridine. -7-yl]decyl ⁇ -2-methylpropionic acid (69).
  • Step A Perchloric acid (4 drops) was added to a mixture containing compound 74 (128 mg, 0.484 mmol), NBS (95 mg, 0.534 mmol) and DMF (7 mL), and the mixture was stirred at room temperature overnight. After adding water (25 mL), the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with brine (30 mL) .
  • Step F For the experimental procedure of Step B, see Step F in Example 1, to obtain 2-[(3-bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indenyl]-2-methylpropane Acid (77).
  • the 5-bromo-4-methylpyridin-2-amine is subjected to a ring-closing reaction with chloroacetaldehyde, and then subjected to a coupling reaction with methyl 2-acetylindol-2-methylpropionate, and the obtained product is hydrolyzed and hydrolyzed. And acidification, to give 2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid (84), the specific experimental operation see implementation Steps D, E, and F in Example 1 and Step A in Example 21.
  • In vitro inhibition assays for hURAT1 transport uric acid can be used to screen for potentially active compounds with reduced blood uric acid.
  • the present invention pre-establishes a stable cell line highly expressing hURAT1, and blocks the ability of the stable cell line to take up radioisotope-labeled uric acid by detecting the compound.
  • Lesinurad was used as a positive control (purchased from Chengdu Yichao Medical Technology Co., Ltd.) to evaluate the inhibitory activity of the compound on hURAT1 transport uric acid.
  • HEK293 cell line human embryonic kidney cells, purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
  • plasmid pCMV6-hURAT1 purchased from Origene Technologies, Inc.
  • G418 was purchased at a concentration of 500 ⁇ g/ml.
  • Engineering Bioengineering (Shanghai) Co., Ltd.) carried out resistance screening and obtained stable plants.
  • the membrane surface of this cell strain highly expresses the hURAT1 transporter, and can be used as a model cell for screening a hURAT1 transport uric acid inhibitor in vitro according to the present invention (Toxicological Sciences, 2009, 113(2): 305-314.).
  • hURAT1 stably transfected cells were inserted into the coated cell plates at 2 ⁇ 10 5 /well, and cultured for 3 days at 37 ° C in a 5% CO 2 incubator.
  • buffer HBSS 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.3 mM calcium gluconate, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 5.6 mM glucose, 25 mM HEPES (all purchased from Shanghai Sinopharm) Group Chemical Reagent Co., Ltd.)
  • HBSS buffer 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.3 mM calcium gluconate, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 5.6 mM glucose, 25 mM HEPES (all purchased from Shanghai Sinopharm) Group Chemical Reagent Co., Ltd.)
  • HBSS buffer 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.3 mM calcium gluconate, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 5.6
  • the inhibition rate of the compound for hURAT1 transport uric acid is as follows:
  • the compound Compared with the positive drug Lesinurad, the compound had a good inhibitory effect on hURAT1 transport uric acid in HEK293 transfected cells at a concentration of 500 nM.
  • Example 26 Cytotoxicity test of compound 6 against human hepatoma cells HepG2, human normal liver cells L-02 and WRL-68
  • the cytotoxic effect of the compound 6 provided by the present invention on human hepatoma cells HepG2, human normal liver cells L-02 and WRL-68 was tested using Lesinurad as a positive control.
  • Human hepatoma cell HepG2 purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
  • human normal liver cell L-02 purchased from Wuhan Punosi Biotechnology Co., Ltd.
  • human normal liver cell WRL-68 by Nanjing University of Life Sciences Huihui
  • DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL streptomycin, purchased from Thermo Fisher Scientific Inc
  • the tank is cultured to a cell density of about 90%.
  • DMEM medium was used to prepare test compound 6 with different concentration gradient or control drug Lesinurad (purchased from Chengdu Yichao Medical Technology Co., Ltd.), and added as 100 ⁇ L/well as test compound well or control drug well; according to 100 ⁇ L/ The wells were added to the DMEM medium as a negative control well. Incubate for 96 h at 37 ° C in a 5% CO 2 incubator.
  • the plate 96 is set 37 °C, 5% CO 2 incubator 3h.
  • the half-inhibitory concentration (IC 50 ) was greater than 1000 ⁇ M, and the IC 50 of Lesinurad to HepG2 cells was 135.0 ⁇ M.

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Abstract

La présente invention concerne un nouvel inhibiteur URAT1 et son application pharmaceutique. L'inhibiteur est un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable du composé, un groupe radicalaire du composé étant défini par la description. Le composé représenté par la formule (I) peut être utilisé pour préparer un produit pharmaceutique favorisant l'excrétion de l'acide urique, spécifiquement destiné à la production d'un produit pharmaceutique de traitement ou de prévention de l'hyperuricémie ou de la goutte.
PCT/CN2017/079251 2016-04-05 2017-04-01 Nouvel inhibiteur urat1 et son application pharmaceutique WO2017173965A1 (fr)

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US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators

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CN109608432B (zh) * 2018-12-17 2022-10-11 江苏艾立康医药科技有限公司 作为urat1抑制剂的噻吩类衍生物
CN111943957B (zh) * 2019-05-17 2023-01-06 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途
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CN114621136B (zh) * 2020-12-09 2023-11-07 江苏正大清江制药有限公司 吡啶巯乙酸类化合物及其制备方法、药学衍生物或配剂以及应用

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CN114315705B (zh) * 2020-09-29 2024-02-20 杭州中美华东制药有限公司 一类urat1抑制剂及其制备方法与用途
US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators

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