WO2016173503A1 - 含二芳基甲烷结构的羧酸类urat1抑制剂、制备方法及其用途 - Google Patents

含二芳基甲烷结构的羧酸类urat1抑制剂、制备方法及其用途 Download PDF

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WO2016173503A1
WO2016173503A1 PCT/CN2016/080468 CN2016080468W WO2016173503A1 WO 2016173503 A1 WO2016173503 A1 WO 2016173503A1 CN 2016080468 W CN2016080468 W CN 2016080468W WO 2016173503 A1 WO2016173503 A1 WO 2016173503A1
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compound
formula
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/CN2016/080468
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English (en)
French (fr)
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赵桂龙
刘巍
商倩
周植星
王玉丽
李玉荃
张海枝
李川
刘长鹰
刘钰强
谢亚非
吴景卫
陈会慧
徐为人
汤立达
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天津药物研究院有限公司
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Priority to CN201680021837.1A priority Critical patent/CN107531649B/zh
Priority to KR1020177034556A priority patent/KR102431920B1/ko
Priority to ES16785934T priority patent/ES2832501T3/es
Priority to US15/570,151 priority patent/US10584104B2/en
Priority to MYPI2017704103A priority patent/MY195694A/en
Priority to EP16785934.7A priority patent/EP3290408B1/en
Priority to AU2016253911A priority patent/AU2016253911B2/en
Publication of WO2016173503A1 publication Critical patent/WO2016173503A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to the field of drugs for hyperuricemia and gout.
  • the present invention relates to a class of carboxylic acid uric acid transporter 1 (URAT1) inhibitors containing a diarylmethane structure, a process for the preparation thereof, and a pharmaceutical composition containing the same, and a pharmaceutical composition thereof Use on.
  • URAT1 carboxylic acid uric acid transporter 1
  • Gout is a chronic metabolic disease characterized by hyperuricemia and uric acid monosodium salt (MSU) depositing in joints and other parts, causing pain and pain, mainly due to sputum metabolism disorder and/or uric acid discharge disorder.
  • MSU uric acid monosodium salt
  • the current treatments for hyperuricemia and gout mainly include: i) anti-inflammatory analgesic drugs for the control of symptoms such as joint swelling and pain in acute joints of gout, such as colchicine and non-steroidal anti-inflammatory drugs (NSAID); a drug for inhibiting uric acid production, such as xanthine oxidase (XO) inhibitors such as allopurinol, oxycodone and febuxostat; iii) drugs for uric acid excretion, such as probenecid and benzbroma Long et al; iv) uric acid decomposing drugs that rapidly lower blood uric acid during acute gout attacks, such as uricase and PEGylated glutamatease.
  • NSAID non-steroidal anti-inflammatory drugs
  • XO xanthine oxidase
  • drugs for uric acid excretion such as probenecid and benzbroma Long et al
  • colchicine has common adverse reactions such as diarrhea, vomiting, abdominal cramps, and is the first indication of its toxicity, the effective dose and its dose causing gastrointestinal symptoms Similar; probenecid can cause renal colic and renal dysfunction; benzbromarone has the risk of causing fulminant hepatitis; allopurinol has adverse reactions such as liver and bone marrow toxicity and allergy; uric acid enzyme preparation is administered by injection, The patient's compliance is not as good as oral preparations. It is only suitable for lowering blood uric acid during acute gout attacks and should not be used for long-term treatment.
  • Urate transporter 1 is located on the brush border of the epithelial cells of the proximal convoluted tubules of the kidney. It is an important uric acid transporter found in the kidney in recent years and is responsible for the reabsorption of uric acid in the kidney (Enomoto, A. ; Kimura, H.; et al. Nature, 2002, vol 417, 447-452). Obviously, inhibition of URAT1 will inhibit the reabsorption of uric acid in the kidney, increase the excretion of uric acid in the urine, and thus reduce the blood uric acid and control the onset of gout. Preclinical and clinical studies by Lesinurad et al. have demonstrated the efficacy of URAT1 inhibitors in the treatment of hyperuricemia and gout (Fleischmann, R.; Kerr, B.; et al. Rheumatology, 2014, vol 53, 2167-2174). ).
  • Lesinurad is an oral drug developed by Ardea that inhibits URAT1 and excretes uric acid from the blood. It was first developed from Valeant's antiviral drug RDEA806 (shown below). Lesinurad has submitted a listing application to the EMA (US2013345271 and WO2014008295) and its ownership is already owned by Astra Zeneca.
  • the present invention discloses a class of carboxylic acid URAT1 inhibitors containing a diarylmethane structure, which are useful in the preparation of a therapeutic drug for hyperuricemia and gout.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Compositions and their use in the treatment of gout and hyperuricemia are particularly preferred.
  • the compound of the present invention having the formula (I) has the following structural formula:
  • R 1 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, F, Cl, Br, I, CN, NO 2 , SR 4 and OR 4 ;
  • R 2 is selected from H, F, Cl, Br and I;
  • R 3 is selected from the group consisting of H and C 1 -C 4 alkyl;
  • X is selected from S and CH 2 ; wherein R 4 is selected from C 1 -C 10 alkyl.
  • R 1 is selected from the group consisting of H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, F, Cl, Br, CN, NO 2 and OR 4 ;
  • R 2 is selected from H, F, Cl , Br and I;
  • R 3 is selected from H and Me;
  • X is selected from S and CH 2 ; wherein R 4 is selected from C 1 -C 4 alkyl.
  • the compound of the formula (I) of the present invention can be synthesized by the following route.
  • I-A can be synthesized using the following routes:
  • Compound II can be a commercially available chemical starting material or can be prepared according to conventional methods in the art.
  • Compound II is reacted with CuCN to obtain compound III, wherein X 1 is selected from Cl, Br and I; compound III is reduced by LiAlH 4 to obtain compound IV; compound IV is reacted with thiophosgene in the presence of a base to obtain compound V; Firstly, it is added with formyl hydrazide, and the obtained intermediate VI is treated with a base to be cyclized to obtain a compound VII; and the compound VII is reacted with a halogenated acid ester VIII in the presence of a base to obtain a compound IX wherein X 2 is selected from Cl, Br and I, R 5 is selected from a C 1 -C 10 alkyl group; Compound IX is treated with a halogenating agent to give compound X, wherein X 3 is selected from the group consisting of F, Cl, Br, I, and the halogenating agent is selected from the group consisting of XeF 2 , N- Chlorosuccinimide (NCS), N-bro
  • I-B can be synthesized using the following routes:
  • Compound XI can be a commercially available chemical starting material or can be prepared according to conventional methods in the art.
  • the hydrazide XI and the N,N-dimethylformamide dimethyl acetal XII are first heated to obtain the intermediate XIII. Without isolation, the naphthylmethylamine IV is directly reacted with the acid catalyzed, and the ring is obtained.
  • R 6 is selected from C 1 -C 10 alkyl; compound XVIII is treated with a halogenating agent to give compound XIX wherein X 4 is selected from the group consisting of F, Cl, Br, I, and the halogenating agent is selected from the group consisting of XeF 2 , N- Chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dibromohydantoin and dichlorohydantoin; compound XIX or compound XVIII alkaline hydrolysis to obtain compound IB; IB compound salified with a base to give a salt thereof IBS corresponding pharmaceutically acceptable salts wherein the cation M represents a carboxylic acid; wherein R 1 to R 3 are as previously defined.
  • Pharmaceutically acceptable salts of the compounds of formula (I) according to the invention include, but are not limited to, various inorganic bases, for example, NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , Sr(OH) 2 Pharmacologically acceptable, Al(OH) 3 or the like, or an inorganic carbonate such as Na 2 CO 3 , K 2 CO 3 , MgCO 3 , CaCO 3 , SrCO 3 or the like, or an organic base such as an amino acid or the like Salt.
  • various inorganic bases for example, NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , Sr(OH) 2 Pharmacologically acceptable, Al(OH) 3 or the like, or an inorganic carbonate such as Na 2 CO 3 , K 2 CO 3 , MgCO 3 , CaCO 3 , SrCO 3 or the like, or an organic base such as an amino acid or the like Salt.
  • the present invention also provides the use of a compound of the formula (I) according to the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of gout and/or hyperuricemia.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention having the structure of formula (I) or a pharmaceutically acceptable salt thereof, together with a suitable carrier or excipient.
  • the compounds of formula (I) according to the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
  • the pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, an injection, and the like.
  • the solid and liquid oral preparations include: tablets, dispersible tablets, enteric coated tablets, chewable tablets, orally disintegrating tablets, dragees, granules, dry powders, capsules, and solutions.
  • the injection includes: a water injection needle, a small needle, a large infusion, a lyophilized powder needle, and the like.
  • the pharmaceutically or foodly acceptable adjuvant is selected from the group consisting of fillers, binders, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, and coatings. Clothing material, or other excipients.
  • the filler comprises one or a combination of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate and microcrystalline cellulose
  • the binder includes sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, a composition of one or more of hydroxypropylcellulose, methylcellulose, polyethylene glycol, pharmaceutically acceptable ethanol, and water; said disintegrant comprising starch, crosslinked polyoxyketone, crosslinked carboxymethyl A combination of one or more of sodium cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and an effervescent disintegrant.
  • the invention also provides the use of a compound of the formula (I) according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a URAT1 inhibitor.
  • the present invention also provides a method of treating gout and/or hyperuricemia comprising administering to a subject in need thereof a compound having the structure of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, or The pharmaceutical composition of the present invention.
  • the compound of the formula (I) of the present invention has a strong URAT1 inhibitory effect, and is generally significantly stronger than the prior art UAT1 inhibitor in which the triazole and the naphthalene ring are directly linked by a covalent bond. It can be used as an active ingredient in the preparation of a therapeutic drug for gout and hyperuricemia.
  • the activity of the compound of the general formula (I) of the present invention was verified by inhibiting the absorption test of 14 C-labeled uric acid by cells expressing URAT1 in vitro.
  • the compounds of the formula (I) according to the invention are effective over a relatively wide dosage range. For example, a daily dose of about 1 mg to 1000 mg per person is divided into one or several administrations.
  • the dosage at which the compound of the general formula (I) of the present invention is actually administered can be determined by a doctor according to the relevant circumstances.
  • reaction mixture was poured into ice water (500 mL), stirred, and extracted with CH 2 Cl 2 (200mL ⁇ 3 ). The combined organic phase was extracted, washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (800 mL) and then stirred at room temperature for 5 hr.
  • the obtained mixture was suction filtered to remove solids, and the obtained filtrate was washed with water (500 mL ⁇ 5) and dried over anhydrous Na 2 SO 4 .
  • reaction mixture was stirred slowly and carefully poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (200mL ⁇ 3 ). The combined organic phase was extracted, washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was slowly and carefully poured into stirred ice water (200mL), stirred, the organic phase was separated, the aqueous phase was extracted with CH 2 Cl 2 (100mL ⁇ 2 ). The combined organic phases were washed successively with 2% diluted hydrochloric acid (200mL) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was evaporated to dryness on a rotary evaporator, the residue that is obtained VI-1 crude product to DMF (60mL) was dissolved, was added solid K 2 CO 3 (3.04g, 22mol ). The reaction mixture was stirred at 50 ° C until the reaction was complete (usually 5 hours).
  • reaction mixture was cooled to room temperature, it was poured into ice water (300 mL), stirred, and adjusted to pH 5-6 with hydrochloric acid, and extracted with CH 2 Cl 2 (100 mL ⁇ 5). The combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was poured into ice water (200mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 3 ). The combined organic phases were washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • 4-pentenoylhydrazine XI-1 was synthesized according to literature methods (Gilchrist, T.L.; et al. Synthesis, 1983, 153-154). 4-pentenoylhydrazine XI-1 (11.41 g, 100 mmol) and N,N-dimethylformamide dimethyl acetal XII (11.92 g, 100 mmol) dissolved in acetonitrile (230 mL) and heated at 50 ° C Stir until TLC finds the reaction is complete (usually about 0.5-1 hours).
  • reaction mixture was poured into ice water (700 mL of), stirred, and extracted with CH 2 Cl 2 (200mL ⁇ 3 ).
  • the organic phase was combined and washed with a Na 2 S 2 O 3 solution and 5% brine, dried over anhydrous Na 2 SO 4 .
  • the reaction mixture was evaporated to dryness on a rotary evaporator, and the obtained residue was dissolved in methanol (20mL ⁇ 2) and then evaporated to remove water in the residue, and the residue obtained was further dried on a vacuum oil pump in a water bath at 35 ° C
  • the sodium salt of IA-1, IA-1-S was obtained as white solid, 0.431 g, yield 98%.
  • Example 1 sample 100mg Microcrystalline cellulose 30mg Pregelatinized starch 20mg Polyvinylpyrrolidone 3mg Magnesium stearate 2mg talcum powder 1mg
  • the active ingredient, pregelatinized starch and microcrystalline cellulose are sieved, thoroughly mixed, added to polyvinylpyrrolidone solution, mixed, softened, sieved, wet granules, dried at 50-60 ° C, magnesium stearate
  • the talc is pre-screened and then added to the above granules to be encapsulated.
  • Example 2 sample 300mg Microcrystalline cellulose 80mg Pregelatinized starch 70mg Polyvinylpyrrolidone 6mg Carboxymethyl starch sodium salt 5mg Magnesium stearate 2mg talcum powder 2mg
  • the active ingredient, pregelatinized starch and microcrystalline cellulose are sieved, thoroughly mixed, added to polyvinylpyrrolidone solution, mixed, softened, sieved, wet granules, dried at 50-60 ° C, and carboxymethyl starch
  • the sodium salt, magnesium stearate and talc are previously sieved and then added to the above granules for tableting.
  • Example 51 sample 10mg Citric acid 100mg NaOH Moderate (pH 4.0-5.0) Distilled water 50mL
  • distilled water In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4.0-5.0, add 0.2g activated carbon, stir at room temperature for 20 minutes, filter, filtrate, medium Control the concentration of the solution, according to 5mL per amp bottle, high temperature sterilization for 30 minutes, that is, the injection.
  • Preparation process the main drug and the auxiliary material are respectively passed through a 100 mesh sieve, thoroughly mixed, and then the prescription auxiliary material is fully mixed with the main drug. Adding binder to soft material, 14 mesh sieve granules, drying at 55 ° C, 12 The sieve is sifted and the bag is repackaged.
  • Example 53 sample 2.0g Polosham 1.0g Sodium hydroxide 0.2g Tannic acid QS Mannitol 26.0g lactose 23.0g Water for Injection 100mL
  • Preparation process Take 80 mL of water for injection, add the main drug, mannitol, lactose, poloxamer to dissolve, then add 1 mol/L of citric acid to adjust the pH to 7.0-9.0, and add water to 100 mL. Add 0.5g of activated carbon, stir at 30 ° C for 20 minutes, decarbonize, filter and sterilize by microfiltration membrane, the filtrate is divided into 1mL each, after pre-freezing for 2 hours, freeze under vacuum for 12 hours, to the sample After the temperature reached room temperature, it was dried for another 5 hours to obtain a white loose mass, which was obtained by sealing.
  • the expression cells (HEK293) and mock cells stably expressing the URAT1 gene were inoculated into a lysine-coated 24-well culture plate at a cell seeding density of 1 ⁇ 10 5 cells/well at 37 ° C, 5%.
  • the cells were cultured for 2 days in an incubator of CO 2 and saturated humidity.
  • the culture medium in the culture plate was removed, and the cultured cells were washed twice with DPBS, and incubated in 37° CD PBS buffer for 10 min, followed by 500 ⁇ L of radiolabeled probe substrate ([8- 14 C] uric acid) and 10 ⁇ M.
  • the test compound (or blank) solution was substituted for DPBS, the concentration of [8- 14 C] uric acid was 30 ⁇ M, and the radiation intensity per well was 0.867 ⁇ Ci. After 2 min, the reaction was stopped with ice bath DPBS buffer and washed 3 times. Then, 500 ⁇ L of 0.1 mol/L NaOH was added to each well to lyse the cells, and the lysate was extracted into a scintillation vial, and 3 mL of scintillation fluid (Aquasol-2) was added and used.
  • the Tri-Carb 2910TR liquid scintillation meter (PerkinElmer, Waltham, USA) measures the radioactivity in the sample.
  • Inhibition rate (control-test compound) / (control-mock) ⁇ 100%
  • control no radioactivity corresponding to the pores of the compound to be tested
  • Test compound radiation intensity corresponding to the pore of the test compound
  • the compound of the present invention has a strong inhibitory effect on URAT1 and is generally more strongly represented by lesinurad, compound A (US2014005136) and compound B (CN201510008880.1).
  • the URAT1 inhibitor in which triazole and naphthalene ring are directly linked by covalent bonds, can be used as a drug for the treatment of gout and hyperuricemia.

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Abstract

本发明涉及高尿酸血症和痛风的药物领域。具体而言，本发明涉及一类具有通式(I)的含二芳基甲烷结构的羧酸类尿酸转运体1(URAT1)抑制剂及其制备方法、及含有它们的药物组合物以及它们在制备治疗高尿酸血症和痛风中的应用。其中，R1选自H，C1-C10的烷基，C3-C10的环烷基，F，Cl，Br，I，CN，NO2，SR4或OR4；R2选自H，F，Cl，Br或I；R3选自H或C1-C4的烷基；X选自S或CH2；其中R4选自C1-C10的烷基。

Description

含二芳基甲烷结构的羧酸类URAT1抑制剂、制备方法及其用途 技术领域
本发明涉及高尿酸血症和痛风的药物领域。具体地讲，本发明涉及对上述疾病具有治疗作用的一类含二芳基甲烷结构的羧酸类尿酸转运体1(URAT1)抑制剂、其制备方法，以及含有它们的药物组合物以及在医药上的用途。
背景技术
痛风是一种以高尿酸血症和尿酸单钠盐(MSU)沉积在关节等部位而引起痛疼为主要特征的慢性代谢性疾病，主要原因为嘌呤代谢紊乱和/或尿酸排出障碍。目前全球痛风患者有数千万。
目前的高尿酸血症及痛风治疗药物主要包括：i)用于痛风急性发作关节肿胀、痛疼等症状控制的消炎止痛药物，如秋水仙碱和非甾体抗炎药物(NSAID)等；ii)用于抑制尿酸生成的药物，如别嘌醇、奥昔嘌醇和非布索坦等黄嘌呤氧化酶(XO)抑制剂；iii)用于尿酸排泄的药物，如丙磺舒和苯溴马隆等；iv)用于急性痛风发作时迅速降低血尿酸的尿酸分解药，如尿酸酶(uricase)以及聚乙二醇化的尿酸酶(pegloticase)。但是，这些药物均具有比较严重的副作用，如秋水仙碱具有腹泻、呕吐、腹痛性痉挛等常见的不良反应，并且是其毒性的第一指征，治疗有效剂量与其引起胃肠道症状的剂量相近；丙磺舒能引发肾绞痛和肾功能损害；苯溴马隆有引起爆发性肝炎的危险；别嘌醇具有肝脏及骨髓毒性和变态反应等不良反应；尿酸酶制剂为注射给药，病人的顺应性不如口服制剂，只适应于急性痛风发作时降低血尿酸，不宜用于长期治疗。
尿酸转运体1(urate transporter 1,URAT1)位于肾脏近曲小管的上皮细胞的刷状缘上，是近年来发现的位于肾脏的重要尿酸转运体，负责肾脏中尿酸的重吸收(Enomoto,A.；Kimura,H.；et al.Nature,2002,vol 417,447-452)。很显然，抑制URAT1就会抑制肾脏中尿酸的重吸收、增加尿液中尿酸的排泄，进而达到降低血尿酸和控制痛风发作的目的。Lesinurad等的临床前研究和临床研究已经证实了URAT1抑制剂在治疗高尿酸血症和痛风方面的疗效(Fleischmann,R.；Kerr,B.；et al.Rheumatology,2014,vol 53,2167-2174)。
Lesinurad(RDEA 594)是一种由Ardea公司研制的可以抑制URAT1而排出血液中尿酸的口服药物，最早由Valeant的抗病毒药物RDEA806发展而来(如下图所示)。Lesinurad目前已经向EMA递交了上市申请(US2013345271和WO2014008295)，其所有权已经属于Astra Zeneca。
Figure PCTCN2016080468-appb-000001
本发明公开了一类含二芳基甲烷结构的羧酸类URAT1抑制剂，这些化合物可用于制备高尿酸血症和痛风的治疗药物。
发明内容
本发明的一个目的是提供一种具有通式(I)的URAT1抑制剂及其药学上可以接受的盐。
本发明的另一个目的是提供制备具有通式(I)的化合物及其药学上可以接受的盐的方法。
本发明的再一个目的是提供含有通式(I)的化合物及其药学上可以接受的盐作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在治疗痛风和高尿酸血症方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式(I)的化合物具有下述结构式：
Figure PCTCN2016080468-appb-000002
其中，R1选自H，C1-C10的烷基，C3-C10的环烷基，F，Cl，Br，I，CN，NO2，SR4和OR4；R2选自H，F，Cl，Br和I；R3选自H和C1-C4的烷基；X选自S和CH2；其中R4选自C1-C10的烷基。
优选以下通式(I)化合物，
其中，R1选自H，C1-C4的烷基，C3-C6的环烷基，F，Cl，Br，CN，NO2和OR4；R2选自H，F，Cl，Br和I；R3选自H和Me；X选自S和CH2；其中R4选自C1-C4的烷基。
更加优选的具有通式(I)的化合物如下，
Figure PCTCN2016080468-appb-000003
Figure PCTCN2016080468-appb-000004
Figure PCTCN2016080468-appb-000005
本发明所述通式(I)化合物可以通过以下路线合成。
(1)当X＝S时，本发明所述通式(I)化合物即为I-A：
Figure PCTCN2016080468-appb-000006
I-A可以采用下列路线合成：
Figure PCTCN2016080468-appb-000007
化合物II可以为市售化学原料或者按照本领域内常规方法制备。
化合物II与CuCN反应，得到化合物III，其中X1选自Cl、Br和I；化合物III被LiAlH4还原，得到化合物IV；化合物IV在碱存在下与硫光气反应，得到化合物V；化合物V先与甲酰肼加成，得到的中间体VI用碱处理而环化得到化合物VII；化合物VII与卤代酸酯VIII在碱存在下反应，得到化合物IX，其中X2选自Cl、Br和I，R5选自C1-C10的烷基；化合物IX使用卤化剂处理，得到化合物X，其中X3选自F、Cl、Br、I，所述卤化剂选自XeF2、N-氯代琥珀酰亚胺(NCS)、N-溴代琥珀酰亚胺(NBS)、N-碘代琥珀酰亚胺(NIS)、二溴海因和二氯海因；化合物X或化合物IX经碱性水解即可得到化合物I-A；化合物I-A与碱成盐得到其对应的药学上可以接受的盐I-A-S，其中M代表羧酸盐中的阳离子；其中R1至R3的定义如前所述。
(2)当X＝CH2时，本发明所述通式(I)化合物即为I-B：
Figure PCTCN2016080468-appb-000008
I-B可以采用下列路线合成：
Figure PCTCN2016080468-appb-000009
化合物XI可以为市售化学原料或者按照本领域内常规方法制备。
酰肼XI和N,N-二甲基甲酰胺二甲基缩醛XII先加热反应，得到中间体XIII，不用分离，直接与后加入的萘甲胺IV在酸催化下反应，关环得到三氮唑化合物XIV；化合物XIV经过双羟化得到邻二醇化合物XV；XV用NaIO4处理得到醛XVI；化合物XVI进一步氧化，得到对应的酸XVII；化合物XVII与醇R6OH反应得到对应的酯XVIII，R6选自C1-C10的烷基；化合物XVIII使用卤化剂处理，得到化合物XIX，其中X4选自F、Cl、Br、I，所述卤化剂选自XeF2、N-氯代琥珀酰亚胺(NCS)、N-溴代琥珀酰亚胺(NBS)、N-碘代琥珀酰亚胺(NIS)、二溴海因和二氯海因；化合物XIX或化合物XVIII经碱性水解即可得到化合物I-B；化合物I-B与碱成盐得到其对应的药学上可以接受的盐I-B-S，其中M代表羧酸盐中的阳离子；其中R1至R3的定义如前所述。
本发明所述式(I)化合物的药学上可接受的盐包括，但不限于与各种无机碱，例如，NaOH、KOH、Mg(OH)2、Ca(OH)2、Sr(OH)2、Al(OH)3等，或无机碳酸盐，例如Na2CO3、K2CO3、MgCO3、CaCO3、SrCO3等，或有机碱，例如氨基酸等，所生成的药学上可接受的盐。
本发明还提供了本发明所述的具有通式(I)结构的化合物或其药学上可以接受的盐在制备治疗痛风和/或高尿酸血症的药物中的应用。
本发明还提供了一种药物组合物，其含有本发明所述的具有通式(I)结构的化合物或其药学上可以接受的盐，以及适当的载体或赋形剂。
本发明所述式(I)化合物，可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。所述固体及液体口服制剂包括：片剂、分散片、肠溶片、咀嚼片、口崩片、糖衣剂、颗粒剂、干粉剂、胶囊剂和溶液剂。所述的注射剂包括：注射用水针、小针、大输液、冻干粉针等。
本发明的组合物，所述的药学或食品学上可接受辅料选自：填充剂、粘合剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料、或其它赋形剂。
其中，所述填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙和微晶纤维素中的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、 羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇和水的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚微酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲纤维素钠和泡腾崩解剂的一种或几种的组合物。
本发明还提供了本发明所述的具有通式(I)结构的化合物或其药学上可以接受的盐在制备URAT1抑制剂中的应用。
本发明还提供了一种治疗痛风和/或高尿酸血症的方法，包括给予需要的受试者本发明所定义的具有通式(I)结构的化合物或其药学上可以接受的盐、或本发明所述的药物组合物。
本发明所述通式(I)化合物具有很强的URAT1抑制作用，且普遍性地显著强于现有技术中的三氮唑和萘环直接以共价键相连为结构特征的URAT1抑制剂，可作为有效成分用于制备痛风和高尿酸血症的治疗药物。本发明所述通式(I)化合物的活性是通过体外抑制表达了URAT1的细胞对14C-标记的尿酸的吸收实验来验证的。
本发明的通式(I)化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-1000mg/人范围内，分为一次或数次给药。实际服用本发明通式(I)化合物的剂量可由医生根据有关的情况来决定。
实施发明的最佳方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1化合物I-A-1的合成
Figure PCTCN2016080468-appb-000010
步骤1.化合物II-1的合成
市售化合物II-A(8.41g,50mmol)溶于乙腈(150mL)中，室温下搅拌，加入NBS(10.68g,60mmol)。所得反应混合物在室温下搅拌过夜，此时TLC显示反应完成。
反应混合物倾倒入冰水(500mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物II-1，无色油状物，10.01g,产率81％。1H NMR(DMSO-d6,400MHz),δ8.43-8.47(m,1H),8.13-8.17(m,1H),7.75(d,1H,J＝7.6Hz),7.66-7.72(m,2H),7.15-7.17(m,1H),2.34-2.41(m,1H),1.03-1.08(m,2H),0.69-0.73(m,2H).
步骤2.化合物III-1的合成
化合物II-1(9.89g,40mmol)和CuCN(10.75g,120mmol)加入到DMF(200mL)中，在氮气保护下在130℃下加热搅拌，直到TLC显示反应完成(一般10小时)。
反应混合物冷却到室温后，加入乙酸乙酯(800mL)稀释，而后在室温下继续搅拌5小时。所得混合物抽滤除去固体，所得滤液使用水洗涤(500mL×5)，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的 残余物经过柱层析纯化，得到产物III-1，白色固体，6.49g,产率84％。熔点48.5-49.5℃；1H NMR(DMSO-d6,400MHz),δ8.51-8.54(m,1H),8.09-8.11(m,1H),8.01(d,1H,J＝7.2Hz),7.73-7.81(m,2H),7.31(d,1H,J＝7.6Hz),2.51-2.56(m,1H),1.11-1.15(m,2H),0.79-0.83(m,2H).
步骤3.化合物IV-1的合成
化合物III-1(6.18g,32mmol)溶于干燥的THF(100mL)中，搅拌，在冰水浴冷却下慢慢分批加入LiAlH4(1.90g,50mmol)，加完后反应混合物在室温下继续搅拌5小时，而后在氮气保护下升温回流1小时，此时TLC检测发现反应完成。
反应混合物小心慢慢倾倒入搅拌的冰水(400mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物IV-1，无色油状物，5.56g,产率88％。1H NMR(DMSO-d6,400MHz),δ8.39-8.42(m,1H),8.10-8.13(m,1H),7.52-7.59(m,2H),7.42(d,1H,J＝7.2Hz),7.20(d,1H,J＝7.2Hz),4.14(s,2H),2.31-2.37(m,1H),1.83(bs,2H),1.00-1.05(m,2H),0.65-0.69(m,2H).
步骤4.化合物V-1的合成
化合物IV-1(5.33g,27mmol)和二异丙基乙基胺(DIPEA,11.63g,90mmol)溶于干燥的CH2Cl2(100mL)中，所得溶液在冰水浴冷却下搅拌，而后慢慢滴加CSCl2(3.45g,30mmol)，滴加完毕后，所得溶液在室温下继续搅拌1小时，此时TLC检查发现反应完成。
反应混合物小心慢慢倾倒入搅拌的冰水(200mL)中，搅拌，分出有机相，水相用CH2Cl2(100mL×2)萃取。合并有机相，依次用2％稀盐酸(200mL)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物V-1，白色固体，5.36g,产率83％。熔点67.5-69℃；1H NMR(DMSO-d6,400MHz),δ8.45-8.49(m,1H),8.05-8.09(m,1H),7.63-7.68(m,2H),7.48(d,1H,J＝7.2Hz),7.25(d,1H,J＝7.2Hz),5.33(s,2H),2.36-2.43(m,1H),1.03-1.07(m,2H),0.70-0.74(m,2H).
步骤5.化合物VII-1的合成
化合物V-1(5.27g,22mol)以THF(50mL)溶解，室温下搅拌，加入甲酰肼(1.32g,22mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为VI-1的粗品，以DMF(60mL)溶解，加入固体K2CO3(3.04g,22mol)。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(300mL)中，搅拌，以盐酸调节pH＝5-6，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物VII-1，白色固体，4.70g,产率76％(V-1→VII-1)。熔点188-189.5℃；1H NMR(DMSO-d6,400MHz),δ13.83 (brs,1H),8.45-8.48(m,1H),8.28(s,1H),8.14-8.16(m,1H),7.58-7.65(m,2H),7.24(d,1H,J＝7.2Hz),7.19(d,1H,J＝7.2Hz),5.56(s,2H),2.36-2.42(m,1H),1.03-1.08(m,2H),0.69-0.73(m,2H).
步骤6.化合物IX-1的合成
化合物VII-1(4.50g,16mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K2CO3(6.63g,48mmol)和溴乙酸甲酯VIII-1(2.75g,18mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物IX-1，白色固体，5.26g,产率93％。熔点123-125℃；1H NMR(DMSO-d6,400MHz),δ8.62(s,1H),8.46-8.49(m,1H),8.08-8.10(m,1H),7.61-7.67(m,2H),7.22(d,1H,J＝7.2Hz),6.94(d,1H,J＝7.6Hz),5.66(s,2H),4.06(s,2H),3.62(s,3H),2.36-2.43(m,1H),1.03-1.07(m,2H),0.69-0.72(m,2H).
步骤7.化合物X-1的合成
化合物IX-1(3.53g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物X-1，无色油状粘稠物，3.89g,产率90％。1H NMR(DMSO-d6,400MHz),δ8.48-8.50(m,1H),8.13-8.16(m,1H), 7.66-7.71(m,2H),7.18(d,1H,J＝7.6Hz),6.43(d,1H,J＝7.2Hz),5.69(s,2H),4.06(s,2H),3.61(s,3H),2.36-2.41(m,1H),1.02-1.06(m,2H),0.67-0.71(m,2H).
步骤8.化合物I-A-1的合成
化合物X-1(3.46g,8mmol)加入甲醇(50mL)中，室温下搅拌，加入由LiOH·H2O(0.84g,20mmol)和水(3mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物I-A-1，白色固体，2.78g,产率83％。熔点153.5-154.5℃；1H NMR(DMSO-d6,400MHz),δ13.10(brs,1H),8.48-8.50(m,1H),8.13-8.16(m,1H),7.66-7.71(m,2H),7.18(d,1H,J＝7.6Hz),6.43(d,1H,J＝7.2Hz),5.68(s,2H),3.96(s,2H),2.36-2.40(m,1H),1.02-1.06(m,2H),0.67-0.71(m,2H).
实施例2化合物I-B-1的合成
Figure PCTCN2016080468-appb-000011
步骤1.化合物XIV-1的合成
4-戊烯酰肼XI-1系按照文献方法合成(Gilchrist,T.L.；et al.Synthesis,1983,153-154)。4-戊烯酰肼XI-1(11.41g,100mmol)和N,N-二甲基甲酰胺二甲基缩醛XII(11.92g,100mmol)溶于乙腈(230mL)中，在50℃下加热搅拌，直到TLC发现反应完成(通常0.5-1小时左右)。
反应完成后，反应混合物稍冷，在旋转蒸发仪上浓缩至原来体积的1/3，此时得到了XIII-1的溶液。往其中加入4-环丙基萘甲胺IV-1(19.73g,100mmol)和冰醋酸(230mL)，反应混合物在氮气保护下在120℃下搅拌过夜，TLC检查发现反应完成。
反应混合物冷却后，倾倒到冰水(1000mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，依次用1％稀盐酸(200mL)、饱和NaHCO3(200mL)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XIV-1，25.49g,产率84％。MS,m/z＝304([M+H]+).
步骤2.化合物XV-1的合成
化合物XIV-1(24.27g,80mmol)溶于THF/H2O(240mL,体积比90/10)的混合溶剂中，室温下搅拌，加入N-甲基吗啉N-氧化物(NMMO,18.74g,160mmol)和0.16M的OsO4的80％的叔丁醇水溶液(25mL,4mmol)。反应混合物在室温下搅拌过夜，TLC检查发现反应完成。
反应混合物抽滤，滤液倾倒入冰水(600mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，依次用Na2S2O3溶液(200mL)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XV-1，23.75g,产率88％。MS,m/z＝338([M+H]+).
步骤3.化合物XVI-1的合成
化合物XV-1(23.28g,69mmol)溶于THF/H2O(330mL,体积比90/10)的混合溶剂中，室温下搅拌，慢慢分批加入NaIO4(44.28g,207mmol)，加完后，反应混合物在室温下继续搅拌，直到TLC跟踪反应完成。
反应混合物倾倒入冰水(700mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，依次用Na2S2O3溶液和5％食盐水洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XVI-1，16.67g,产率91％。MS,m/z＝306([M+H]+).
步骤4.化合物XVII-1的合成
化合物XVI-1(18.32g,60mmol)溶于THF(400mL)中，室温下搅拌，加入2-甲基-2-丁烯(126.23g,1800mmol)，而后慢慢加入由NaClO216.28g,180mmol)和NaH2PO4(43.19g,360mmol)溶于水(100mL)而配制而成的溶液。加完后，反应混合物在室温下继续搅拌，直到TLC检查反应完成(通常6小时)。
反应混合物倾倒入冰水(800mL)中，搅拌，用浓盐酸调节pH＝2-3，用CH2Cl2(200mL×3)萃取。合并萃取有机相，用清水洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XVII-1，16.58g,产率86％。MS,m/z＝320([M-H]-).
步骤5.化合物XVIII-1的合成
化合物XVII-1(14.46g,45mmol)溶于干燥的THF(145mL)中，室温下搅拌，加入甲醇(14.42g,450mmol)，而后依次加入N-(3-二甲氨基丙基)-N'-乙基碳化二亚胺盐酸盐(EDCI,11.50g,60mmol)和4-二甲氨基吡啶(DMAP,11.00g,90mmol)。加完后，反应混合物在室温下搅拌过夜，然后再升温回流3小时，TLC检查发现反应完成。
反应混合物倾倒入冰水(500mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，依次用5％稀盐酸(300mL)、饱和Na2CO3溶液(100mL)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XVIII-1，12.38g,产率82％。MS,m/z＝336([M+H]+).
步骤6.化合物XIX-1的合成
化合物XVIII-1(3.35g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物XIX-1，3.77g,产率91％。MS,m/z＝414、416([M+H]+).
步骤7.化合物I-B-1的合成
化合物XIX-1(3.31g,8mmol)加入甲醇(50mL)中，室温下搅拌，加入由LiOH·H2O(0.84g,20mmol)和水(3mL)配成的溶液，而后室温下搅拌，直到 TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物I-B-1，2.59g,产率81％。MS,m/z＝398、400([M-H]-).
实施例3-50
参考实施例1和实施例2的方法，合成了下列具有通式I的化合物。
Figure PCTCN2016080468-appb-000012
Figure PCTCN2016080468-appb-000013
Figure PCTCN2016080468-appb-000014
Figure PCTCN2016080468-appb-000015
Figure PCTCN2016080468-appb-000016
Figure PCTCN2016080468-appb-000017
Figure PCTCN2016080468-appb-000018
Figure PCTCN2016080468-appb-000019
Figure PCTCN2016080468-appb-000020
Figure PCTCN2016080468-appb-000021
实施例53由化合物I-A-1合成其钠盐I-A-1-S
Figure PCTCN2016080468-appb-000022
化合物I-A-1(0.418g,1mmol)溶于甲醇(5mL)中，室温下搅拌，慢慢加入由NaOH(0.400g,1mmol)和水(1mL)配制的溶液，加完后，反应混合物在室温下继续搅拌10分钟。
反应混合物在旋转蒸发仪上蒸干，得到的残余物用甲醇(20mL×2)溶解后再蒸干以便除去残余物中的水，得到的残余物进一步在真空油泵上在35℃的水浴中干燥12小时，得到I-A-1的钠盐I-A-1-S，白色固体，0.431g,产率98％。1H NMR(DMSO-d6,400MHz),δ8.47-8.50(m,1H),8.15-8.17(m,1H),7.67-7.70(m,2H),7.18(d,1H,J＝7.2Hz),6.35(d,1H,J＝7.2Hz),5.66(s,2H),3.65(s,2H),2.34-2.41(m,1H),1.01-1.05(m,2H),0.68-0.71(m,2H).
实施例54-72由实施例2-52中部分化合物合成其钠盐
参照实施例53的方法，可以将下表所列具有通式I的化合物转化为其对应的钠盐I-S。
Figure PCTCN2016080468-appb-000023
Figure PCTCN2016080468-appb-000024
Figure PCTCN2016080468-appb-000025
Figure PCTCN2016080468-appb-000026
实施例75
组分 用量/粒
实施例1样品 100mg
微晶纤维素 30mg
预胶化淀粉 20mg
聚乙烯吡咯烷酮 3mg
硬脂酸镁 2mg
滑石粉 1mg
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中，装胶囊，即得。
实施例76
组分 用量/片
实施例2样品 300mg
微晶纤维素 80mg
预胶化淀粉 70mg
聚乙烯吡咯烷酮 6mg
羧甲基淀粉钠盐 5mg
硬脂酸镁 2mg
滑石粉 2mg
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将羧甲基淀粉钠盐，硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中压片。
实施例77
组分 用量/50mL
实施例51样品 10mg
柠檬酸 100mg
NaOH 适量(调pH4.0-5.0)
蒸馏水 50mL
在蒸馏水中，先加入蒸馏水和柠檬酸，搅拌溶解和后，再加入样品，微热使溶解，调pH值为4.0-5.0，加0.2g活性碳，室温下搅拌20分钟，过滤，滤液，中控测定溶液浓度，按每安瓶5mL分装，高温灭菌30分钟，即得注射液。
实施例78
颗粒剂组分 /100袋
实施例52样品 10.0g
乳糖 55.0g
甘露醇 14.0g
阿司巴甜 0.05g
香精 0.05g
2％羟丙甲纤维素(纯水配制) QS
制备工艺：将主药与辅料分别过100目筛，充分混合，然后称取处方量辅料与主药充分混合。再加入粘合剂制软材，14目筛制粒，55℃干燥，12 目筛整粒，测定袋重包装。
实施例79
组分 用量
实施例53样品 2.0g
泊洛沙姆 1.0g
氢氧化钠 0.2g
枸橼酸 QS
甘露醇 26.0g
乳糖 23.0g
注射用水 100mL
制备工艺：取注射用水80mL，加主药、甘露醇、乳糖、泊洛沙姆搅拌使溶解后，加1mol/L的枸橼酸调节pH至7.0-9.0，补加水至100mL。加入0.5g活性炭，在30℃下搅拌20分钟，脱炭，采用微孔滤膜过滤除菌，滤液按每支1mL进行分装，预冻2小时后，冷冻下减压干燥12小时,至样品温度到室温后，再干燥5小时，制得白色疏松块状物，封口即得。
实施例80化合物体外抑制URAT1分析
(一)待测化合物在10μM浓度下的对URAT1的抑制实验
胰酶消化后，将稳定表达URAT1基因的表达细胞(HEK293)和mock细胞均接种于赖氨酸包被24孔培养盘，细胞接种密度为1×105个/孔，在37℃、5％CO2、饱和湿度的培养箱内培养2天。移去培养板内培养液，将培养细胞用DPBS清洗两次，并在37℃DPBS缓冲液中温浴10min，然后以500μL含有放射性标记的探针底物([8-14C]尿酸)和10μM待测化合物(或者空白)溶液置换DPBS，[8-14C]尿酸的浓度为30μM，每孔放射强度为0.867μCi。2min后，用冰浴DPBS缓冲液终止反应，并清洗3次，然后各孔添加500μL0.1mol/L NaOH裂解细胞，提取裂解液于闪烁瓶中，添加3mL的闪烁液(Aquasol-2)，并用Tri-Carb 2910TR液闪仪(PerkinElmer,Waltham,USA)测定样品中的放射性强度。
使用上述测定的数据根据下列公式计算待测化合物对URAT1的抑制率：
抑制率＝(control-test compound)/(control-mock)×100％
其中：control＝无待测化合物的孔对应的放射性强度
test compound＝待测化合物的孔对应的放射性强度
mock＝未转染URAT1的空白细胞的孔对应的放射性强度
结果汇总见下表1。
Figure PCTCN2016080468-appb-000027
表1化合物在10μM浓度下对URAT1的抑制率结果
Figure PCTCN2016080468-appb-000028
Figure PCTCN2016080468-appb-000029
(二)待测化合物对URAT1的抑制的IC50
使用本实施例中(一)的方法，改变某个具体待测化合物的浓度，设置一系列浓度点(在0.001-10μM之间设置9个浓度点)，从而得到该具体待测化合物在上述9个浓度点下的“抑制率”。根据该待测化合物在不同浓度下的“抑制率”数值使用PRISM软件计算待测化合物对URAT1抑制的的IC50值(见表2)。
表2化合物对URAT1的抑制的IC50
Figure PCTCN2016080468-appb-000030
从上述两个表的结果可以看出，本发明的化合物对URAT1具有很强的抑制作用，且普遍性地显著强于以lesinurad、化合物A(US2014005136)和化合物B(CN201510008880.1)为代表的三氮唑和萘环直接以共价键相连为结构特征的URAT1抑制剂，可以作为制备治疗痛风和高尿酸血症的药物。

Claims (10)

  1. 具有通式(I)结构的化合物或其药学上可以接受的盐，
    Figure PCTCN2016080468-appb-100001
    其中，R1选自H，C1-C10的烷基，C3-C10的环烷基，F，Cl，Br，I，CN，NO2，SR4或OR4；R2选自H，F，Cl，Br或I；R3选自H或C1-C4的烷基；X选自S或CH2；其中R4选自C1-C10的烷基。
  2. 如权利要求1所定义的具有通式(I)结构的化合物或其药学上可以接受的盐，
    其中，R1选自H，C1-C4的烷基，C3-C6的环烷基，F，Cl，Br，CN，NO2或OR4；R2选自H，F，Cl，Br或I；R3选自H或Me；X选自S或CH2；其中R4选自C1-C4的烷基。
  3. 如权利要求1或2所定义的通式(I)结构的化合物或其药学上可以接受的盐，选自下列化合物，
    Figure PCTCN2016080468-appb-100002
    Figure PCTCN2016080468-appb-100003
    Figure PCTCN2016080468-appb-100004
  4. 制备权利要求1-3任一项所定义的具有通式(I)结构的化合物的方法，
    其中当X＝S时，通式I的化合物即为I-A，所述方法包括以下步骤：
    Figure PCTCN2016080468-appb-100005
    化合物II与CuCN反应，得到化合物III，其中X1选自Cl、Br或I；化合物III被LiAlH4还原，得到化合物IV；化合物IV在碱存在下与硫光气反应，得到化合物V；化合物V先与甲酰肼加成，得到的中间体VI用碱处理而环化得到化合物VII；化合物VII与卤代酸酯VIII在碱存在下反应，得到化合物IX，其中X2选自Cl、 Br或I，R5选自C1-C10的烷基；化合物IX使用卤化剂处理，得到化合物X，其中X3选自F、Cl、Br、I，所述卤化剂选自XeF2、N-氯代琥珀酰亚胺(NCS)、N-溴代琥珀酰亚胺(NBS)、N-碘代琥珀酰亚胺(NIS)、二溴海因或二氯海因；化合物X或化合物IX经碱性水解即可得到化合物I-A；化合物I-A与碱成盐得到其对应的药学上可以接受的盐I-A-S，其中M代表羧酸盐中的阳离子；其中R1、R2、R3的定义如权利要求1所述；或者
    当X＝CH2时，通式I的化合物即为I-B，所述方法包括以下步骤：
    Figure PCTCN2016080468-appb-100006
    酰肼XI和N,N-二甲基甲酰胺二甲基缩醛XII先加热反应，得到中间体XIII，不用分离，直接与后加入的萘甲胺IV在酸催化下反应，关环得到三氮唑化合物XIV；化合物XIV经过双羟化得到邻二醇化合物XV；XV用NaIO4处理得到醛XVI；化合物XVI进一步氧化，得到对应的酸XVII；化合物XVII与醇R6OH反应得到对应的酯XVIII，R6选自C1-C10的烷基；化合物XVIII使用卤化剂处理，得到化合物XIX，其中X4选自F、Cl、Br、I，所述卤化剂选自XeF2、N-氯代琥珀酰亚胺(NCS)、N-溴代琥珀酰亚胺(NBS)、 N-碘代琥珀酰亚胺(NIS)、二溴海因或二氯海因；化合物XIX或化合物XVIII经碱性水解即可得到化合物I-B；化合物I-B与碱成盐得到其对应的药学上可以接受的盐I-B-S，其中M代表羧酸盐中的阳离子；其中R1、R2、R3的定义如权利要求1所述。
  5. 权利要求1-3任一项所定义的具有通式(I)结构的化合物或其药学上可以接受的盐在制备治疗痛风和/或高尿酸血症的药物中的应用。
  6. 一种药物组合物，含有如权利要求1-3任一项所述的具有通式(I)结构的化合物或其药学上可以接受的盐，以及适当的载体或赋形剂。
  7. 如权利要求6所述的药物组合物，其中，所述的组合物为固体口服制剂、液体口服制剂或注射剂。
  8. 如权利要求7所述的药物组合物，其中，所述固体及液体口服制剂包括：分散片、肠溶片、咀嚼片、口崩片、胶囊、颗粒剂、口服溶液剂，所述注射剂制剂包括注射用水针、注射用冻干粉针、大输液、小输液。
  9. 权利要求1-3任一项所定义的具有通式(I)结构的化合物或其药学上可以接受的盐在制备URAT1抑制剂中的应用。
  10. 一种治疗痛风和/或高尿酸血症的方法，包括给予需要的受试者权利要求1-3中任一项所定义的具有通式(I)结构的化合物或其药学上可以接受的盐、或权利要求6-8中任一项所述的药物组合物。
PCT/CN2016/080468 2015-04-30 2016-04-28 含二芳基甲烷结构的羧酸类urat1抑制剂、制备方法及其用途 WO2016173503A1 (zh)

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KR1020177034556A KR102431920B1 (ko) 2015-04-30 2016-04-28 디아릴메탄 구조를 함유하는 카르복실산 urat1 억제제, 그 제조 방법 및 용도
ES16785934T ES2832501T3 (es) 2015-04-30 2016-04-28 Inhibidor del ácido carboxílico URAT1 que contiene estructura de diarilmetano, método de preparación y uso del mismo
US15/570,151 US10584104B2 (en) 2015-04-30 2016-04-28 Carboxylic acid URAT1 inhibitor containing diarylmethane structure, preparation method and use thereof
MYPI2017704103A MY195694A (en) 2015-04-30 2016-04-28 Carboxylic Acid URAT1 Inhibitor Containing Diarylmethane Structure, Preparation Method and use Thereof
EP16785934.7A EP3290408B1 (en) 2015-04-30 2016-04-28 Carboxylic acid urat1 inhibitor containing diarylmethane structure, preparation method and use thereof
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