WO2016155653A1 - 轴手性异构体及其制备方法和制药用途 - Google Patents

轴手性异构体及其制备方法和制药用途 Download PDF

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WO2016155653A1
WO2016155653A1 PCT/CN2016/078239 CN2016078239W WO2016155653A1 WO 2016155653 A1 WO2016155653 A1 WO 2016155653A1 CN 2016078239 W CN2016078239 W CN 2016078239W WO 2016155653 A1 WO2016155653 A1 WO 2016155653A1
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compound
group
acid
chiral
pharmaceutically acceptable
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PCT/CN2016/078239
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French (fr)
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王建非
张静
张龙
张杨
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to EP16771408.8A priority Critical patent/EP3279188B1/en
Priority to JP2017552028A priority patent/JP6725530B2/ja
Priority to ES16771408T priority patent/ES2835924T3/es
Priority to US15/563,132 priority patent/US10183915B2/en
Publication of WO2016155653A1 publication Critical patent/WO2016155653A1/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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the present invention relates to two axial chiral isomers and useful pharmaceutically acceptable salts thereof, processes for their preparation, and pharmaceutical uses of the two axial chiral isomers or pharmaceutical compositions thereof.
  • the present invention provides a left- or right-handed compound of formula (I), or a pharmaceutically acceptable salt thereof, which is present as a single-axis chiral isomer or in an enriched form of an axial chiral isomer.
  • the content of one of the axial chiral isomers is ⁇ 60%, preferably ⁇ 70%, more preferably ⁇ 80%, more preferably ⁇ 90%, and most preferably ⁇ 95%.
  • the invention also provides a compound of formula (II):
  • the excess of the chiral isomer of formula (II) is > 95%.
  • the invention also provides a compound of formula (III):
  • the excess of the chiral isomer of formula (III) is > 95%.
  • the invention also provides a process for the preparation of the above compounds comprising the route of formula (IV):
  • Y is selected from O, NH or N(W); W is selected from an alkyl group, which is optionally substituted by 1, 2 or 3 of halogen, OH, CN or NH 2 ;
  • the above chiral separation refers to SFC separation
  • the above W is selected from C 1-6 alkyl groups, which are optionally substituted by 1, 2 or 3 of halogen, OH, CN or NH 2 .
  • the above W is selected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, and trifluoroethyl.
  • the invention also provides a process for the preparation of the above compounds comprising the route of formula (V):
  • L is selected from O, NH or N(R);
  • R represents a chiral group selected from a chiral alkyl group, a heteroalkyl group, an aralkyl group, a heteroarylalkyl group, an aryl group;
  • the chiral group is optionally substituted by 1, 2 or 3 of halogen, OH, CN or NH 2 ;
  • the achiral separation refers to recrystallization, thin layer chromatography separation, column chromatography separation, rapid column separation, and preparative column separation using achiral fillers.
  • the invention also provides a process for the preparation of the above compounds comprising the route of formula (VI):
  • X is selected from the group consisting of F, Cl, Br, I, sulfonate; and R' is selected from the group consisting of F, Cl, Br, I or OH.
  • the hydrolysis is carried out under strong base conditions.
  • the strong base is preferably selected from LiOH, NaOH, or KOH.
  • R is preferably selected from
  • the brominating reagent is Br 2 /base.
  • the base in the bromination reagent is preferably selected from the group consisting of pyridine, triethylamine, or DIPEA.
  • the sulfonate is selected from the group consisting of mesylate, p-toluenesulfonate, p-nitrobenzenesulfonate or triflate.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a composition as described above for the preparation of a medicament for treating a disorder associated with abnormal blood uric acid levels.
  • the invention also provides a method of treating a condition associated with abnormal blood uric acid levels comprising administering to a subject a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition as a medicament for treating a disorder associated with abnormal blood uric acid level.
  • Lesinurad specifically refers to a compound of formula (I):
  • the "left- or right-handed compound of formula (I)" may be a single-axis chiral isomer of the compound of formula (I) or a mixture enriched in one of the chiral chiral isomers.
  • “Enriched in one chiral chiral isomer” means that the content of one of the chiral chiral isomers is ⁇ 100%, and ⁇ 60%, preferably ⁇ 70%, more preferably ⁇ 80%, more preferably ⁇ 90%, Most preferably ⁇ 95%.
  • the excess of the chiral isomer refers to the difference between the relative percentages of the two axial chiral isomers. For example, if one of the chiral chiral isomers is 90% and the other axial chiral isomer is 10%, the axial chiral isomer excess is 80%.
  • the preparation route or the examples described in the examples is not limited to the single-axis chiral isomer defined by the structural formula, but also includes the case where the single-axis chiral isomer is enriched.
  • (+) means right-handed, (-) means left-handed, and ( ⁇ ) means racemic.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), they Fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein a carbon atom (eg, a methylene group) has been replaced by, for example, an oxygen atom.
  • alkyl groups such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • DIPEA diisopropylethylamine
  • OTos stands for p-toluenesulfonate
  • OMs stands for mesylate.
  • pharmaceutically acceptable as used in the present invention is directed to those compounds, materials, compositions and/or dosage forms which are within the scope of sound medical judgment and are suitable for contact with human and animal tissues. Use without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, ethanol Acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ).
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • Lesinurad has optical isomerism caused by chiral axes, and further found that (+)-Lesinurad and (-)-Lesinurad are very stable at room temperature and in plasma, so we have reason to develop a single axis chirality of Lesinurad. isomer.
  • the present invention reports in detail the stability data of two axial chiral isomers (+)-Lesinurad and (-)-Lesinurad of the present invention in solid powders, in conventional organic solutions and in plasma solutions, and stably transfects the URAT1 gene.
  • the transport of labeled uric acid by the HEK293 cell line was Evaluation of the degree of inhibition of the compound, and pharmacokinetic parameters of (+)-Lesinurad and (-)-Lesinurad in rats.
  • (+)-Lesinurad and (-)-Lesinurad solids are stable under normal storage conditions and in solution; the transport of labeled uric acid to HEK293 cell lines stably transfected with URAT1 gene
  • the in vitro activity of (+)-Lesinurad was significantly better than that of (-)-Lesinurad, which was a more in vivo active chiral isomer and better than racemic ( ⁇ )-Lesinurad.
  • the route type (V) or the formula (VI) does not employ chiral separation, thereby reducing the cost.
  • Figure 1 Stereoscopic ellipsoid of a single molecule of compound 12A;
  • Figure 2 Stereoscopic ellipsoid of compound 12A bimolecular
  • Figure 3 Cell stacking diagram of compound 12A along the a-axis direction
  • Figure 4 Stereoscopic ellipsoid of a single molecule of compound 12B;
  • Figure 5 Stereoscopic ellipsoid of compound 12B bimolecular
  • Figure 6 Cell stacking diagram of compound 12B along the a-axis direction.
  • Compound 12 was synthesized by the method reported in the patent CN103524440A or the patent W2009070740.
  • Compound 12A (150.00 mg, 346.96 umol) and Compound 12B (152.00 mg, 351.58 umol) were isolated.
  • Compound 10 was synthesized by the method reported in the patent CN10352440A.
  • Compound 10 (50.00 mg, 187.02 umol, 1.00 eq)
  • Compound 14 54.56 mg, 222.42 umol, 1.20 eq
  • potassium carbonate 31.02 mg, 224.42 umol, 1.20 eq
  • N,N-dimethylformamide 10.00 mL
  • Test Example 1 Evaluation of the degree of inhibition of the transport of labeled uric acid by HEK293 cell line stably transfected with URAT1 gene
  • HEK293 cell line (urate transporter protein) gene using a stably transfected URAT-1 Assay
  • Compound IC 50 values inhibition of reabsorption of uric acid.
  • URAT-1 (HEK293) cell line HEK293 cells stably transfected with URAT-1 gene (cell line constructed by Shanghai WuXi PharmaTech Development Co., Ltd.);
  • DMEM medium Invitrogen 11965118
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • Na pyruvate Invitrogen 113600070
  • 300 ug/mL G418 Gabco 10131
  • HBSS buffer (Invitrogen, 14025126);
  • 0.1M NaOH solution prepared by NaOH dry powder (Jiangsu Qiangsheng Chemical Co., Ltd. 20090206);
  • step 2) Transfer the 5 uL DMSO solution of step 1) to 120 ⁇ l of HBSS buffer and dilute 25 times.
  • step 3 Add 10 ⁇ L of the dilution of step 2) to a 24-well cell plate and incubate for 15 minutes at 37 ° in a 5% CO 2 incubator. The final concentration of DMSO was 0.2%. Cell control wells: no compound, only 0.2% DMSO.
  • the 14C-labeled uric acid solution was diluted and added to the cell plate to a final concentration of 50 ⁇ M. Incubate for 10 minutes at 37 degrees in a 5% CO 2 incubator. After discarding the supernatant, the cells were washed twice with HBSS buffer. A 0.1 M NaOH solution was added to the cells for lysis. The cell lysate was collected in a liquid flash tube, and after adding the liquid flash, the signal value was read using a liquid scintillation counter Tri-Carb.
  • (+)-Lesinurad is superior to (-)-Lesinurad in multiple parallel tests, and it is an axially chiral isomer with higher activity in vitro, and is superior to racemic ( ⁇ ). -Lesinurad.
  • test compound 20 mg was taken and placed in a 5 mL brown transparent stoppered reagent bottle and stored in a nitrogen cabinet (15 ° C) protected from light. After pre-set storage time, accurately weigh about 2mg test compound, add ethanol, prepare 1mg/mL ethanol solution, use high performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LCMS) and supercritical fluid Chromatography (SFC) detects the purity and chiral purity of the compound.
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectrometry
  • SFC supercritical fluid Chromatography
  • Test Example 4 Stability evaluation of compounds in DMSO solution
  • test compound A certain amount was accurately weighed and added to DMSO to prepare a DMSO solution.
  • the DMSO solution of the compound was placed in a heated oil bath and stirred.
  • a certain amount of DMSO solution was diluted with ethanol, and the purity and chiral purity of the compound were determined by high performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LCMS) and supercritical fluid chromatography (SFC).
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectrometry
  • SFC supercritical fluid chromatography
  • Test Example 5 Evaluation of stability of compounds in rat and human plasma
  • the frozen plasma in the -40 ° C refrigerator was thawed at room temperature, then incubated in a 37 ° C water bath for 5-10 min; centrifuged at 4,000 rpm for 5 minutes to remove impurities and lipids in the plasma.
  • the plasma pH was tested and, if necessary, the pH was adjusted to 7.4 ⁇ 0.1.
  • the 10 mM stock solution was diluted with DMSO to an intermediate concentration of 400 ⁇ M.
  • the dilution procedure was: 4 ⁇ L of 10 mM stock solution was added to 96 ⁇ L of DMSO.
  • stop solution stop solution containing 200 ng/mL tolbutamaide and 20 ng/mL buspirone 50% ACN/MeOH solution
  • the decrease in the test compound was evaluated as the ratio of the peak area of the compound to the area of the internal standard peak. After plasma incubation, the retention rate at each time point was calculated as follows:
  • % residual ratio 100* (peak area ratio at a specific time point / peak area ratio at time T0)
  • SD rats were used as test animals, and rats were given IV (intravenous injection) by LC/MS/MS method, and ( ⁇ )-Lesinurad, (+)-Lesinurad and (-)-Lesinurad were given by PO (gavage).
  • the drug concentrations of ( ⁇ )-Lesinurad, (+)-Lesinurad and (-)-Lesinurad in plasma were determined at different times, and the pharmacokinetic behavior of the compounds of the present invention in rats was investigated, and their pharmacokinetic characteristics were evaluated.
  • the IV dose was 2 mg/kg
  • the administration volume was 2 mL/kg
  • the PO dose was 10 mg/kg
  • the administration volume was 5 mL/kg.
  • Group IV was collected 250 ⁇ L before and after 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, placed in an anticoagulant tube of K2-EDTA, centrifuged at 3000 rpm for 15 minutes, and plasma was separated. Store at 80 ° C.
  • the PO group was collected before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and the other operations were the same as the IV group.
  • the content of the test compound in the plasma of IV after PO administration was determined by LC/MS/MS.
  • the analytical method has a linear range of 6.00-18000 nM and a lower limit of quantification of 6.00 nM; plasma samples are pretreated with precipitated proteins for analysis.
  • (+)-Lesinurad and (-)-Lesinurad showed similar pharmacokinetics in SD-rats, similar to ( ⁇ )-Lesinurad.
  • No interconversion of the two axial chiral isomers was observed in vivo, maintaining a stable single-axis chiral isomer within the circulating system.

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Abstract

本发明公开了两种轴手性异构体及其可用药盐，其制备方法，以及这两种轴手性异构体或其药物组合物的制药用途。

Description

轴手性异构体及其制备方法和制药用途 发明领域
本发明涉及两种轴手性异构体及其可用药盐，其制备方法，以及这两种轴手性异构体或其药物组合物的制药用途。
发明背景
Lesinurad(CAS:878672-00-5,RDEA594)作为一种降血尿酸试剂，是由Ardea Biosciences Inc公司在专利(WO2009070740)里首次报道的，其合成路线如下。
合成路线1：
Figure PCTCN2016078239-appb-000001
在随后的多篇专利中(WO2011085009,WO2011126852,WO201159732,WO2012050589,WO2012092395,WO2014008295)，Ardea Biosciences Inc公司对Lesinurad及其钠盐的合成生产，与秋水仙碱(colchicines)，非布索坦(Febuxostat)和别嘌呤醇(Allopurinol)等药物的联合用药都做了详尽的报道。
中国专利CN103524440A也报道了另外一种合成Lesinurad及其中间体的方法，如下。
合成路线2：
Figure PCTCN2016078239-appb-000002
已经报道的这些专利都没有明确提及Lesinurad是具有轴手性的一对手性旋光异构体的混合物，都没有具体报道详细的分离技术和详细的手性合成技术，以及这一对手性旋光异构体的具体参数。
发明内容
本发明提供了左旋或右旋的式(Ⅰ)化合物或其药学上可接受的盐，其以单一轴手性异构体形式或富含一种轴手性异构体形式存在。
Figure PCTCN2016078239-appb-000003
本发明的一个方案中，其中一种轴手性异构体的含量≥60％，优选≥70％，更优选≥80％，更优选≥90％，最优选≥95％。
本发明还提供了式(Ⅱ)化合物：
Figure PCTCN2016078239-appb-000004
本发明的一个方案中，式(Ⅱ)轴手性异构体过量≥95％。
本发明还提供了式(Ⅲ)化合物：
Figure PCTCN2016078239-appb-000005
本发明的一个方案中，式(Ⅲ)轴手性异构体过量≥95％。
本发明还提供了制备上述化合物的方法，其包括式(Ⅳ)所示路线：
Figure PCTCN2016078239-appb-000006
其中，Y选自O、NH或N(W)；W选自烷基，其任选地被卤素、OH、CN或NH2中的1、2或3个所取代；
优选地，上述手性分离是指SFC分离；
优选地，上述W选自C1-6烷基，其任选地被卤素、OH、CN或NH2中的1、2或3个所取代。
优选地，上述W选自甲基、乙基、丙基、三氟甲基、三氟乙基。
本发明还提供了制备上述化合物的方法，其包括式(Ⅴ)所示路线：
Figure PCTCN2016078239-appb-000007
其中L选自O、NH或N(R)；
R代表手性基团，其选自手性的烷基、杂烷基、芳烷基、杂芳烷基、芳基；
所述手性基团任选地被卤素、OH、CN或NH2中的1、2或3个所取代；
优选地，所述非手性分离是指重结晶、薄层色谱分离、柱层析分离、快速过柱机分离、使用非手性填料的制备色谱柱分离。
本发明还提供了制备上述化合物的方法，其包括式(Ⅵ)所示路线：
Figure PCTCN2016078239-appb-000008
其中，X选自F、Cl、Br、I、磺酸酯；R’选自F、Cl、Br、I或OH。
本发明制备方法的一个方案中，所述水解是在强碱条件下进行。
本发明制备方法的一个方案中，所述强碱优选自LiOH、NaOH、或者KOH。
本发明制备方法的一个方案中，所述R选自苯烷基或
Figure PCTCN2016078239-appb-000009
所述苯烷基中烷基上的C任选地被N、O、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O)2、C(＝O)NH、S(＝O)NH、S(＝O)2NH或NHBoc中的一个或多个所替代。
本发明制备方法的一个方案中，R优选自
Figure PCTCN2016078239-appb-000010
Figure PCTCN2016078239-appb-000011
本发明制备方法的一个方案中，所述溴化试剂为Br2/碱。
本发明制备方法的一个方案中，所述溴化试剂中的碱优选自吡啶、三乙胺、或DIPEA。
本发明制备方法的一个方案中，所述磺酸酯选自甲磺酸酯、对甲基苯磺酸酯、对硝基苯磺酸酯或三氟甲磺酸酯。
本发明还提供了一种药物组合物，包括治疗有效量的上述化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物在制备治疗血尿酸水平异常相关病症的药物上的应用。
本发明还提供了一种治疗血尿酸水平异常相关病症的方法，包括给予治疗对象治疗有效量的上述化合物或其药学上可接受的盐或上述组合物。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物作为治疗血尿酸水平异常相关病症的药物的应用。
术语定义
本发明中，除非另有规定，“Lesinurad”特指式(Ⅰ)化合物:
Figure PCTCN2016078239-appb-000012
“左旋或右旋的式(Ⅰ)化合物”可以是式(Ⅰ)化合物的单一轴手性异构体，也可以是富含一种轴手性异构体的混合物。
“富含一种轴手性异构体”指其中一种轴手性异构体的含量＜100％，且≥60％，优选≥70％，更优选≥80％，更优选≥90％，最优选≥95％。
轴手性异构体的过量指两种轴手性异构体相对百分数之间的差值。例如，其中一种轴手性异构体的含量为90％，另一种轴手性异构体的含量为10％，则轴手性异构体过量为80％。
式(Ⅱ)和(Ⅲ)化合物分别是式(Ⅰ)化合物的两种绝对构型，
Figure PCTCN2016078239-appb-000013
分别是
Figure PCTCN2016078239-appb-000014
的两种绝对构型，
Figure PCTCN2016078239-appb-000015
分别是
Figure PCTCN2016078239-appb-000016
的两种绝对构型，
Figure PCTCN2016078239-appb-000017
分别是
Figure PCTCN2016078239-appb-000018
的两种绝对构型，
Figure PCTCN2016078239-appb-000019
分别是
Figure PCTCN2016078239-appb-000020
的两种绝对构型，其结构可经单晶X射线衍射确证。
但是，为了便于表述，制备路线或者实施例中所述
Figure PCTCN2016078239-appb-000021
Figure PCTCN2016078239-appb-000022
Figure PCTCN2016078239-appb-000023
所指代的内容不限于结构式所限定的单一轴手性异构体，也包括富含该单一轴手性异构体的情况。
(+)表示右旋，(-)表示左旋，(±)表示外消旋。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们 稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。
术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
DIPEA代表二异丙基乙胺；OTos代表对甲苯磺酸酯；OMs代表甲磺酸酯。
本发明所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇 酸、氢溴酸、盐酸、氢碘酸盐、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明的进步：
我们发现Lesinurad具有手性轴引起的光学异构现象，并进一步发现(+)-Lesinurad和(-)-Lesinurad在常温下和血浆中都非常稳定，因此我们有理由开发出Lesinurad的单一轴手性异构体。
本发明详细报道了本发明的两个轴手性异构体(+)-Lesinurad和(-)-Lesinurad在固体粉末中、常规有机溶液中和血浆溶液中的稳定性数据，稳定转染URAT1基因的HEK293细胞系对标记尿酸的转运被 化合物抑制程度的评价，以及(+)-Lesinurad和(-)-Lesinurad在大鼠体内的药代动力学参数。从这些数据可以得出结论：(+)-Lesinurad和(-)-Lesinurad固体在常规保存条件下和在溶液中是稳定的；在稳定转染URAT1基因的HEK293细胞系对标记尿酸的转运被化合物抑制程度的评价实验中，(+)-Lesinurad的体外活性明显优于(-)-Lesinurad，是体外活性较高的轴手性异构体，也优于消旋的(±)-Lesinurad；在SD-大鼠体内药代动力学实验中，未观察到(+)-Lesinurad和(-)-Lesinurad在体内的相互转化，在体内(+)-Lesinurad和(-)-Lesinurad保持为稳定的单一轴手性异构体。
本发明的制备方法中，路线式(Ⅴ)或式(Ⅵ)不采用手性分离，从而降低了成本。
附图说明
图1：化合物12A单分子的立体结构椭球图；
图2：化合物12A双分子的立体结构椭球图；
图3：化合物12A沿a轴方向的晶胞堆积图；
图4：化合物12B单分子的立体结构椭球图；
图5：化合物12B双分子的立体结构椭球图；
图6：化合物12B沿a轴方向的晶胞堆积图。
具体实施方式
下面通过实施例和测试例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：(-)-Lesinurad和(+)-Lesinurad的制备
Figure PCTCN2016078239-appb-000024
合成路线：
Figure PCTCN2016078239-appb-000025
步骤1:化合物12A和12B的合成
化合物12参照专利CN103524440A或者专利W2009070740报道方法合成。化合物12(330.00mg,763.31umol)经超临界流体色谱SFC(手性柱:Chiralpak AS(250mm×30mm,5um)；流动相:超临界CO2/乙醇(0.05％DEA)＝70/30；流速:60mL/min；检测波长:220nm)分离得到化合物12A(150.00mg,346.96umol)和化合物12B(152.00mg,351.58umol)。
化合物12A：1H NMR(400MHz,DMSO-d6)δ:8.57(d,J＝8.4Hz,1H),7.78-7.76(m,1H),7.69-7.58(m,2H),7.43(d,J＝7.6Hz,1H),7.13(d,J＝8.0Hz,1H),4.10-4.00(m,4H),2.59-2.51(m,1H),1.17-1.11(m,5H),0.89-0.83(m,2H).SFC(手性柱:Chiralpak AS-H(250mm×4.6mm,5um)；流动相:乙醇(0.05％DEA)/超临界CO2＝5～40％；流速:2.5mL/min；检测波长:254nm)Rt＝4.842min。轴手性异构体过量100％。[α]25 D＝-11.036(c＝9.455mg/mL乙醇溶液)。化合物12A的SXRD图谱数据参见图1～3，具体数据如下：
Figure PCTCN2016078239-appb-000026
Figure PCTCN2016078239-appb-000027
化合物12A原子坐标参数及等价温度因子值
Figure PCTCN2016078239-appb-000028
Figure PCTCN2016078239-appb-000029
化合物12A成键原子的键长和键角值
Figure PCTCN2016078239-appb-000030
Figure PCTCN2016078239-appb-000031
Figure PCTCN2016078239-appb-000032
化合物12A各向异性温度因子值
Figure PCTCN2016078239-appb-000033
Figure PCTCN2016078239-appb-000034
化合物12B：1H NMR(400MHz,DMSO-d6)δ:8.57(d,J＝8.4Hz,1H),7.78-7.76(m,1H),7.68-7.60(m,2H),7.43(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),4.10-4.02(m,4H),2.60-2.51(m,1H),1.20-1.10(m,5H),0.89-0.83(m,2H).SFC(手性柱:Chiralpak AS-H(250mm×4.6mm,5um)；流动相:乙醇(0.05％DEA)/超临界CO2＝5～40％；流速:2.5mL/min；检测波长:254nm)Rt＝5.113min..轴手性异构体过量95.7％。[α]25 D＝9.053(c＝8.645mg/mL乙醇溶液).化合物12B的SXRD图谱数据参见图4～6，具体数据如下：
Figure PCTCN2016078239-appb-000035
化合物12B原子坐标参数及等价温度因子值
Figure PCTCN2016078239-appb-000036
化合物12B成键原子的键长和键角值
Figure PCTCN2016078239-appb-000037
Figure PCTCN2016078239-appb-000038
Figure PCTCN2016078239-appb-000039
Figure PCTCN2016078239-appb-000040
Figure PCTCN2016078239-appb-000041
化合物12B各向异性温度因子值
Figure PCTCN2016078239-appb-000042
Figure PCTCN2016078239-appb-000043
步骤2:化合物(-)-Lesinurad的合成
将化合物12A(106.00mg,245.18umol,1.00eq)溶于四氢呋喃/水/乙醇(3mL,1:1:1)混合溶剂中。在降温到0℃后，加入一水合氢氧化锂(12.35mg,294.22umol,1.20eq)，并在0℃反应一小时。反应完毕后，用稀盐酸(1mol/L)调到pH＝4，在室温下用氮气吹干除去四氢呋喃和乙醇。在残余物中加入水(1mL)，用二氯甲烷(2mL×6)萃取。合并有机相，在室温下用氮气吹干除去二氯甲烷。在残余物中加入乙醇(1mL)溶解残留物，再加入水(10mL)，混匀后冷冻干燥得到白色固体化合物(-)-Lesinurad(94.40mg,233.50umol)。1H NMR(400MHz,DMSO-d6)δ＝8.59(d,J＝8.4Hz,1H),7.79-7.71(t,J＝7.6Hz,1H),7.70-7.61(m,2H),7.45(d,J＝8.0Hz,1H),7.16(d,J＝8.4Hz,1H),3.97(s,2H),2.60-2.55(m,1H),1.18-1.14(d,J＝6.4Hz,2H),0.91-0.86(m,2H).LC/MS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度:5～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.801min；MS m/z:404[M+H]+,406[M+H+2]+.SFC(手性柱:Chiralpak AS-H(250mm×4.6mm,5μm)；流动相:A:超临界CO2,B:甲醇(0.05％DEA)；梯度:5～40％B(5min),40％B(3min),5％B(1.5min)；流速:2.5mL/min；柱温:35℃)Rt＝5.197min。轴手性异构体过量96.5％。[α]22 D＝-3.693(c＝3.030mg/mL乙醇溶液).
步骤3:化合物(+)-Lesinurad的合成
将化合物12B(45.00mg,104.09umol,1.00eq)溶于四氢呋喃/水/乙醇(3mL,1:1:1)混合溶剂中。在降温到0℃后，加入一水合氢氧化锂(5.24mg,124.9umol,1.20eq)，并在0℃反应一小时。反应完毕后，用稀盐酸(1mol/L)调到pH＝4，在室温下用氮气吹干除去四氢呋喃和乙醇。在残余物中加入水(1mL)，用二氯甲烷(2mL×6)萃取。合并有机相，在室温下用氮气吹干除去二氯甲烷。在残余物中加入乙醇(1mL)溶解残留物，再加入水(10mL)，混匀后冷冻干燥得到白色固体化合物(+)-Lesinurad(38.40mg,82.59umol)。1H NMR(400MHz,DMSO-d6)δ＝8.59(d,J＝8.4Hz,1H),7.80-7.72(t,J＝7.2Hz,1H),7.71-7.61(m,2H),7.45(d,J＝7.2Hz,1H),7.16(d,J＝8.0Hz,1H),3.99(s,2H),2.60-2.55 (m,1H),1.20-1.12(dd,J＝8.4Hz,J＝1.6Hz,2H),0.91-0.83(m,2H).LC/MS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.796min；MS m/z:404[M+H]+,406[M+H+2]+.SFC(手性柱:Chiralpak AS-H(250mm×4.6mm,5μm)；流动相:A:超临界CO2,B:甲醇(0.05％DEA)；梯度:5～40％B(5min),40％B(3min),5％B(1.5min)；流速:2.5mL/min；柱温:35℃)Rt＝5.570min..轴手性异构体过量95.9％。[α]25 D＝4.432(c＝3.35mg/mL乙醇溶液).
实施例2：(-)-Lesinurad和(+)-Lesinurad的制备
Figure PCTCN2016078239-appb-000044
合成路线：
Figure PCTCN2016078239-appb-000045
步骤1：化合物14的合成
将化合物13(2.00g,16.37mmol,1.00eq)与吡啶(2.59g,32.74mmol,2.00eq)溶于甲苯(30.00mL)中，混合液在冰水浴下冷却至0℃，加入2-溴乙酰氯(3.09g,19.64mmol,1.20eq)，反应液在0℃下搅拌1小时后析出大量白色固体。反应完全后，过滤，滤饼用二氯甲烷(3mL)洗涤，所得滤液旋干得到 黄色油状粗品。粗品经柱层析纯化(洗脱剂：0～15％乙酸乙酯/石油醚)得到无色油状化合物14(3.20g,13.16mmol,收率80.41％)。1H NMR(400MHz,CDCl3)δ:7.45-7.22(m,6H),6.00-5.92(m,1H),4.07(s,1H),3.85(s,1H),1.63-1.55(d,J＝4Hz,3H).
步骤2：化合物15的合成
化合物10参照专利CN10352440A报道方法合成。将化合物10(50.00mg,187.02umol,1.00eq)，化合物14(54.56mg,224.42umol,1.20eq)和碳酸钾(31.02mg,224.42umol,1.20eq)溶于N,N-二甲基甲酰胺(10.00mL)中，反应液在15℃下搅拌2.5小时。反应完全后，将反应液旋干得到黄色固体粗品。粗品经薄层色谱PTLC纯化(展开剂：50％乙酸乙酯/石油醚)得到无色油状化合物15。LCMS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.888min,MS:m/z 431[M+H]+.SFC(手性柱:Chiralpak AD-3 150×4.6mm I.D.,3um；流动相:A:超临界CO2B:异丙醇(0.05％DEA)；梯度:5～40％B(5.5min),40％B(2min),5％B(2.5min)；流速:2.5mL/min；柱温:35℃；检测波长:254nm)Rt＝5.766min.
步骤3：化合物16A和16B的合成
将化合物15(1.30g,3.03mmol,1.00eq)和吡啶(287.61mg,3.64mmol,1.20eq)溶于乙腈(500.00mL)中，混合液在冰水浴下冷却至0℃，加入液溴(1.45g,9.09mmol,3.00eq)，反应逐渐升至15℃搅拌4小时。反应液用饱和亚硫酸氢钠溶液(20mL)淬灭后，低温旋干得到黄色固体粗品16。粗品16经快速柱层析仪Combi Flash纯化(洗脱剂：0～20％乙酸乙酯/石油醚)，得到化合物16A和16B。
化合物16A:LCMS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.951min,MS:m/z 508[M+H]+,510[M+H+2]+.SFC(手性柱:Chiralcel OJ-H 250×4.6mm I.D.,5um；流动相:异丙醇(0.05％DEA)/超临界CO2(5％～40％)；流速:2.4mL/min；检测波长:220nm)Rt＝8.41min.
化合物16B:LCMS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.946min,MS:m/z 508[M+H]+,510[M+H+2]+.SFC(手性柱:Chiralcel OJ-H 250×4.6mm I.D.,5um；流动相:异丙醇(0.05％DEA)/超临界CO2(5％～40％)；流速:2.4mL/min；检测波长:220nm)Rt＝7.54min.
步骤4：化合物(-)-Lesinurad的合成
将化合物16A(10.00mg,19.67umol,1.00eq)和一水合氢氧化锂(1.65mg,39.34umol,2.00eq)溶于四氢呋喃(1.50mL)和水(1.50mL)中，反应在15℃下搅拌16小时。反应完全后，反应液用稀盐酸(1M)调节至体系pH＝2-3，将反应液旋干得到黄色油状粗品。粗品经制备色谱HPLC分离(制备柱:Phenomenex Synergi C18 150*30mm*4um；流动相:A:水(含0.05％HCl),B:乙腈；梯度38％～68％B (12min)；100％B(2min)；流速:25mL/min)后旋干得到化合物(-)-Lesinurad(白色固体)。LCMS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.786min,MS:m/z 404[M+H]+,406[M+H+2]+.SFC(手性柱:Chiralpak AS-H 250×4.6mm I.D.,5μm；流动相:A:超临界CO2,B:甲醇(0.05％DEA)；梯度:5％～40％B(5min),40％B(3min),5％(1.5min)；流速:2.5mL/min；柱温:35℃)Rt＝5.279min.
步骤5：化合物(+)-Lesinurad的合成
将化合物16B(10.00mg,19.67umol,1.00eq)和一水合氢氧化锂(1.65mg,39.34umol,2.00eq)溶于四氢呋喃(1.50mL)和水(1.50mL)中，反应在15℃下搅拌16小时。反应完全后，反应液用稀盐酸(1M)调节至体系pH＝2-3，将反应液旋干得到黄色油状粗品。粗品经制备色谱HPLC分离(制备柱:Phenomenex Synergi C18 150*30mm*4um；流动相:A:乙腈,B:水(含0.05％HCl)；梯度38％～68％A(12min)；100％A(2min)；流速:25mL/min)后旋干得到到化合物(+)-Lesinurad(白色固体)。LCMS(色谱柱:Ultimate XB-C18,3um,30×2.1mm；流动相:乙腈(0.02％三氟醋酸)的水(0.04％三氟醋酸)溶液；梯度：5％～95％(1.5min)；流速:1.2mL/min；检测波长:220nm&254nm)Rt＝0.787min,MS:m/z 404[M+H]+,406[M+H+2]+.SFC(手性柱:Chiralpak AS-H 250×4.6mm I.D.,5μm；流动相:A:超临界CO2,B:甲醇(0.05％DEA)；梯度:5％～40％B(5min),40％B(3min),5％(1.5min)；流速:2.5mL/min；柱温:35℃)Rt＝5.666min.
测试例1：稳定转染URAT1基因的HEK293细胞系对标记尿酸的转运被化合物抑制程度的评价
1.实验目的：
采用稳定转染URAT-1(尿酸转运蛋白)基因的HEK293细胞系测定化合物抑制尿酸重吸收的IC50值。
2.实验材料:
URAT-1(HEK293)细胞系：稳定转染URAT-1基因的HEK293细胞(细胞系由上海药明康德新药开发有限公司构建)；
细胞培养液：DMEM培养液(Invitrogen 11965118),加10％胎牛血清(FBS,Corning 35076105)、1％丙酮酸钠(Invitrogen 113600070)和300ug/mL G418(Gibco 10131)；
HBSS缓冲液:(Invitrogen,14025126)；
0.1M NaOH溶液:由NaOH干粉(江苏强盛化工有限公司20090206)配制；
14C标记-尿酸溶液(ARC 0513A)；
CO2培养箱:(Thermo)；
液体闪烁发光计数仪Tricarb:(Backman)；
3.实验步骤和方法：
a细胞接种:
1)吸掉细胞培养的培养上清，用10mL PBS洗细胞。
2)加入预热过的胰酶到洗过的细胞培养瓶中，旋转培养瓶使胰酶均匀覆盖培养瓶底部。室温消化。
3)每个T150培养瓶用10－15mL培养液悬浮细胞，吸取0.1mL用台盼蓝溶液稀释2倍计数细胞。
4)用培养液稀释细胞到2.5×105/mL,将稀释好的细胞加入鼠尾胶原包被过的24孔板(800μL/孔,2×105细胞/孔)。置于37度,5％CO2培养箱培养过夜。
b细胞准备：
1)细胞接种于24孔板16-18小时后，弃去上清。每孔加入600μl的HBSS缓冲液，清洗两遍。
2)吸掉HBSS缓冲液后，再向每孔加入180μl的HBSS缓冲液。
c化合物溶液制备、稀释和加样:
1)将化合物粉剂溶解于100％DMSO。然后对化合物以3倍稀释6个点，或10倍稀释2个点，最高起始浓度为50mM。
2)将步骤1)的5uL DMSO溶液转入120μl HBSS缓冲液，稀释25倍。
3)将步骤2)的10μL稀释液加入24孔细胞板，置于37度,5％CO2培养箱孵育15分钟。DMSO终浓度为0.2％。细胞对照孔：不加化合物，只含0.2％DMSO。
d检测：
将14C标记-尿酸溶液稀释加入细胞板，终浓度为50μM。置于37度,5％CO2培养箱孵育10分钟。弃去上清后，用HBSS缓冲液清洗细胞两遍。向细胞加入0.1M NaOH溶液进行裂解。将细胞裂解液收集于液闪管，加入液闪液后，使用液闪计数仪Tri-Carb读取信号值。
e数据处理和分析：
根据发光数据分析化合物对URAT-1抑制效果，计算抑制百分比数据。采用GraphPad Prism软件对抑制百分比(inh﹪)数据进行非线性拟合分析得到IC50值。
4.实验结果见表1：
表1 各实施例对URAT-1抑制效果IC50测试结果
  测试例 IC50
1 (±)-Lesinurad 11.66uM(n＝3)
2 (+)-Lesinurad 3.84uM(n＝3)
3 (-)-Lesinurad 17.21uM(n＝3)
实验结果表明：在多次平行测试中，(+)-Lesinurad的体外活性明显优于(-)-Lesinurad，是体外活性较高的轴手性异构体，也优于消旋的(±)-Lesinurad。
测试例2：化合物固体在常温下的稳定性评价
实验步骤和方法：
取20mg测试化合物，置于5mL棕色透明具塞试剂瓶中，于氮气柜中(15℃)避光保存。在预先设定的保存时间后，准确称取2mg左右测试化合物，加入乙醇，制备成1mg/mL的乙醇溶液，用高效液相色谱(HPLC)或者液质联用色谱(LCMS)和超临界流体色谱(SFC)检测化合物的纯度和手性纯度。实验结果见表2：
表2 固体化合物的稳定性测试结果
Figure PCTCN2016078239-appb-000046
注：SFC分析条件与实施例1中步骤2和步骤3的分析条件相同。
实验结果表明：(+)-Lesinurad和(-)-Lesinurad固体粉末在15℃保存超过80天后，SFC纯度未见变化，仍保持稳定。
测试例3：化合物在乙醇溶液中的稳定性评价
实验步骤和方法：
准确称取一定量测试化合物，加入乙醇，制备成乙醇溶液。将化合物的乙醇溶液置于加热的油浴中搅拌。在检测终点，用高效液相色谱(HPLC)或者液质联用色谱(LCMS)和超临界流体色谱(SFC)检测化合物的纯度和手性纯度。实验结果见表3：
表3 化合物在乙醇溶液中的稳定性测试结果
Figure PCTCN2016078239-appb-000047
注：SFC分析条件与实施例1中步骤2和步骤3的分析条件相同。
实验结果表明：(+)-Lesinurad和(-)-Lesinurad固体在乙醇溶液中加热至37℃和70℃后，SFC纯度未见变化，仍保持稳定。
测试例4：化合物在DMSO溶液中的稳定性评价
实验步骤和方法：
准确称取一定量测试化合物，加入DMSO，制备成DMSO溶液。将化合物的DMSO溶液置于加热的油浴中搅拌。在检测终点，取一定量DMSO溶液用乙醇稀释后，用高效液相色谱(HPLC)或者液质联用色谱(LCMS)和超临界流体色谱(SFC)检测化合物的纯度和手性纯度。实验结果见表4：
表4 化合物在乙醇溶液中的稳定性测试结果
Figure PCTCN2016078239-appb-000048
Figure PCTCN2016078239-appb-000049
Figure PCTCN2016078239-appb-000050
注：SFC分析条件与实施例1中步骤2和步骤3的分析条件相同。
实验结果表明：(+)-Lesinurad和(-)-Lesinurad固体在DMSO溶液中加热至80℃,120℃和160℃后，SFC纯度未见变化，仍保持稳定。
测试例5：化合物在大鼠和人血浆中的稳定性评价
1.实验材料
1.1 测试化合物储存液
(+)-Lesinurad和(-)-Lesinurad
1.2 测试基质
Figure PCTCN2016078239-appb-000051
2.实验步骤与方法
2.1 实验之前，将冻存在-40℃冰箱内的血浆放在室温下解冻，然后在37℃水浴锅内孵育5-10min；4,000rpm离心5分钟，去除血浆内的杂质和脂类。测试血浆pH，有必要的情况下，将pH调节到7.4±0.1。
2.2 10mM储存液用DMSO稀释至中间浓度400μM，稀释步骤为：4μL的10mM储存液加入96μL DMSO。
2.3 孵育样品的制备：3μL的中间浓度溶液(400μM)加入到597μL的空白血浆中，形成终浓度为2μM的孵育样品。将所有时间点(0,10,30,60,120min)的孵育样品在37℃水浴锅中孵育，每个样品做两个重复。
2.4 每到一个时间点从孵育板中取出100μL的孵育样品，加入400μL的终止液(终止液为含有内标200ng/mL tolbutamaide和20ng/mL buspirone 50％ACN/MeOH溶液)沉淀蛋白。将已处理过的所有时间点的样品在摇板机上充分混合。
2.5 离心20min,4,000rpm；取上清100μL，加入200μL超纯水。摇板机上800rpm 10min，然后样品进行LC-MS/MS分析。
3.实验数据分析
以化合物峰面积与内标峰面积的比值来评估待测化合物的减少。血浆孵育之后，计算每个时间点的保留率，公式如下：
％剩余率＝100*(特定时间点的峰面积比值/T0时间点的峰面积比值)
特定时间点：0,10,30,60,120min；T0：孵育之前的样品
4.化合物在大鼠和人血浆中的稳定性结果
实验结果见表5：
表5 各实施例在大鼠和人血浆中的稳定性测试结果
Figure PCTCN2016078239-appb-000052
Figure PCTCN2016078239-appb-000053
实验结果表明：(+)-Lesinurad和(-)-Lesinurad在与人血浆或者SD-大鼠血浆共孵育2小时后仍保持稳定。测试例6：化合物在大鼠体内的药代动力学测试
1.实验目的
以SD大鼠为受试动物，应用LC/MS/MS法测定大鼠IV(静注)，PO(灌胃)给予(±)-Lesinurad，(+)-Lesinurad和(-)-Lesinurad后，不同时刻测定血浆中(±)-Lesinurad，(+)-Lesinurad和(-)-Lesinurad的药物浓度，研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1试验药品
(±)-Lesinurad，(+)-Lesinurad和(-)-Lesinurad
2.2 试验动物
健康成年雄性SD大鼠18只，分成6组(每个化合物各有IV,PO组)，每组3只，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0016。
2.3 药物配制
称取适量样品，加入一定量的纯水中，调节pH7～8，分别制成1mg/mL(过滤后澄清)和2mg/mL(有少许混悬颗粒)用于IV和PO给药。
2.4 给药
SD大鼠18只，分成6组，每组3只，雄性，禁食一夜后分别IV，PO给药。IV剂量为2mg/kg，给药体积为2mL/kg；PO剂量为10mg/kg，给药体积为5mL/kg。
3.实验操作
IV组于给药前及给药后0.083,0.25,0.5,1,2,4,8,24小时采血250μL，置于K2-EDTA的抗凝管中，3000rpm离心15分钟，分离血浆，于-80℃保存。PO组于给药前及给药后0.25,0.5,1,2,4,8,24小时采血，其他操作同IV组。用LC/MS/MS法测定IV，PO给药后大鼠血浆中的待测化合物含量。分析方法的线性范围为6.00-18000nM，定量下限均为6.00nM；血浆样品经沉淀蛋白预处理后进行分析。
4.药代动力学参数结果
实验结果见表6：
表6 各实施例在大鼠体内的药代动力学参数
Figure PCTCN2016078239-appb-000054
实验结果表明：(+)-Lesinurad和(-)-Lesinurad在SD-大鼠体内药代动力学表现相近，与(±)-Lesinurad相似。在体内未观察到两个轴手性异构体的相互转化，在循环体系内保持为稳定的单一轴手性异构体。

Claims (11)

  1. 左旋或右旋的式(Ⅰ)化合物或其药学上可接受的盐，其以单一轴手性异构体形式或富含一种轴手性异构体形式存在。
    Figure PCTCN2016078239-appb-100001
  2. 式(Ⅱ)或式(Ⅲ)化合物或其药学上可接受的盐：
    Figure PCTCN2016078239-appb-100002
  3. 一种根据权利要求1所述的化合物的制备方法，其包括式(Ⅳ)所示路线：
    Figure PCTCN2016078239-appb-100003
    其中，Y选自O、NH或N(W)；W选自烷基、杂烷基、芳烷基、杂芳烷基、芳基、杂芳基，其任选地被卤素、OH、CN或NH2中的1、2或3个所取代；
    优选地，所述手性分离是指SFC分离；
    优选地，W选自C1-6烷基，其任选地被卤素、OH、CN或NH2中的1、2或3个所取代；
    更优选地，W选自甲基、乙基、丙基、三氟甲基、三氟乙基。
  4. 一种根据权利要求1所述的化合物的制备方法，其包括式(Ⅴ)所示路线：
    Figure PCTCN2016078239-appb-100004
    其中L选自O、NH或N(R)；
    R代表手性基团，其选自手性的烷基、杂烷基、芳烷基、杂芳烷基、芳基、杂芳基；
    所述手性基团任选地被卤素、OH、CN或NH2中的1、2或3个所取代；
    优选地，所述非手性分离是指重结晶、薄层色谱分离、柱层析分离、快速过柱机分离、使用非手性填料的制备色谱柱分离。
  5. 根据权利要求4所述的制备方法，其包括式(Ⅵ)所示路线：
    Figure PCTCN2016078239-appb-100005
    其中，X选自F、Cl、Br、I、磺酸酯；R’选自F、Cl、Br、I或OH。
  6. 根据权利要求3、4或5任意一项所述的制备方法，其中所述水解是在强碱条件下进行；所述强碱优选自LiOH、NaOH、或者KOH。
  7. 根据权利要求4或5所述的制备方法，其中所述R选自苯烷基或
    Figure PCTCN2016078239-appb-100006
    所述苯烷基中烷基上的C任选地被N、O、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O)2、C(＝O)NH、S(＝O)NH、、S(＝O)2NH或NHBoc中的一个或多个所替代；
    R优选自
    Figure PCTCN2016078239-appb-100007
    Figure PCTCN2016078239-appb-100008
  8. 根据权利要求5所述的制备方法，其中所述溴化试剂为Br2/碱；所述碱优选自吡啶、三乙胺、或DIPEA。
  9. 根据权利要求5所述的制备方法，其中所述磺酸酯选自甲磺酸酯、对甲基苯磺酸酯、对硝基苯磺酸酯或三氟甲磺酸酯。
  10. 一种药物组合物，包括治疗有效量的根据权利要求1或2任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  11. 根据权利要求1或2任意一项所述的化合物或其药学上可接受的盐或根据权利要求10所述的组合物在制备治疗血尿酸水平异常相关病症的药物上的应用；或
    一种治疗血尿酸水平异常相关病症的方法，包括给予治疗对象治疗有效量的根据权利要求1或2任意一项所述的化合物或其药学上可接受的盐或根据权利要求10所述的组合物；或
    根据权利要求1或2任意一项所述的化合物或其药学上可接受的盐或根据权利要求10所述的组合物作为治疗血尿酸水平异常相关病症的药物的应用。
PCT/CN2016/078239 2015-04-03 2016-04-01 轴手性异构体及其制备方法和制药用途 WO2016155653A1 (zh)

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