[go: up one dir, main page]

WO2020177752A1 - 1,2,4-三唑类化合物及其制法和药物用途 - Google Patents

1,2,4-三唑类化合物及其制法和药物用途 Download PDF

Info

Publication number
WO2020177752A1
WO2020177752A1 PCT/CN2020/078082 CN2020078082W WO2020177752A1 WO 2020177752 A1 WO2020177752 A1 WO 2020177752A1 CN 2020078082 W CN2020078082 W CN 2020078082W WO 2020177752 A1 WO2020177752 A1 WO 2020177752A1
Authority
WO
WIPO (PCT)
Prior art keywords
substitution
mono
ortho
compound
cycloalkyl
Prior art date
Application number
PCT/CN2020/078082
Other languages
English (en)
French (fr)
Inventor
肖志艳
叶菲
杨亚军
田金英
严定安
张晓琳
杨颖�
李雪晨
任龙
闫祯昕
候现新
姜楠
南光磊
Original Assignee
中国医学科学院药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医学科学院药物研究所 filed Critical 中国医学科学院药物研究所
Publication of WO2020177752A1 publication Critical patent/WO2020177752A1/zh

Links

Images

Classifications

    • 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
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to 1,2,4-triazole compounds represented by the general formula I, and their physiologically acceptable salts; pharmaceutical compositions and preparation methods of these compounds, and the preparation of these compounds.
  • 1,2,4-triazole compounds represented by the general formula I and their physiologically acceptable salts
  • pharmaceutical compositions and preparation methods of these compounds and the preparation of these compounds
  • the use in the xanthine oxidase inhibitor, the application in the preparation of drugs for preventing or treating xanthine oxidase related diseases are examples of 1,2,4-triazole compounds represented by the general formula I, and their physiologically acceptable salts; pharmaceutical compositions and preparation methods of these compounds, and the preparation of these compounds.
  • Hyperuricemia is a disease in which the level of uric acid in the blood rises due to uric acid metabolism disorders, which can easily cause other metabolic diseases such as gout.
  • Statistics show that hyperuricemia and the gout caused by it have become the second largest metabolic disease in the world after diabetes. In recent years, with the improvement of people's living standards in our country, the incidence of hyperuricemia and gout has also been increasing year by year, bringing a heavy burden to society and families.
  • High levels of blood uric acid are closely related to many diseases. The first is gout. When the level of uric acid in the body exceeds its solubility limit, urate crystallizes and deposits in joints or soft tissues, causing inflammatory reactions and then gout. Studies have shown that more than 21% of hyperuricemia patients eventually develop gout. In addition, high levels of blood uric acid can also cause many complications. Epidemiological studies have shown that hyperuricemia is closely related to many diseases, such as hypertension, type 2 diabetes, non-alcoholic fatty liver disease, obesity, chronic kidney disease, cardiovascular disease, and stroke.
  • the main ways to reduce the level of uric acid in the body include inhibition of uric acid production and promotion of uric acid excretion. Therefore, the clinically used uric acid-lowering drugs are mainly divided into two categories, namely, Xanthine oxidase (XO) inhibitors that inhibit uric acid production. Purinol, febuxostat, topinostat, etc.) and drugs that promote uric acid excretion. As a key enzyme in the metabolic pathway of uric acid production, xanthine oxidase inhibitors occupy an important position.
  • XO Xanthine oxidase
  • the present invention aims to provide a new 1,2,4-triazole compound, which has high xanthine oxidase inhibitory activity and can be used to treat hyperuricemia and gout caused by hyperuricemia.
  • the technical problem solved by the present invention is to provide a novel 1,2,4-triazole compound represented by formula I, its preparation method, pharmaceutical composition and use in the preparation of xanthine oxidase inhibitors, and It is used for preventing or treating diseases related to hyperuricemia.
  • the present invention adopts the following technical solutions:
  • the first aspect of the technical scheme of the present invention is to provide a 1,2,4-triazole compound represented by the following general formula (I) and a physiologically acceptable salt thereof,
  • Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, indolyl, quinolinyl, naphthyl, and the substituents are each Independently selected from halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, C 1 -C 3 alkanesulfonyl; X is selected from oxygen Or sulfur atom; n is 1, 2, 3, 4 or 5; Y is selected from C 1 -C 6 alkyl substituted amino, C 3 -C 6 cycloalkyl substituted amino, pyrrolyl, piperidinyl , Piperazinyl and morpholinyl; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen
  • Preferred compounds are the compounds represented by general formula (IA) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; Y is selected from C 1 -C 6 alkyl substituted amino group, C 3 -C 6 cycloalkyl substituted amino group, Pyrrolyl, piperidinyl, piperazinyl and morpholinyl; R 1 is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the ortho di-substitution of the X substituent or other Di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl,
  • Preferred compounds are the compounds represented by general formula (IB) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; Y is selected from C 1 -C 6 alkyl substituted amino group, C 3 -C 6 cycloalkyl substituted amino group, Pyrrolyl, piperidinyl, piperazinyl and morpholinyl; R 1 is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 linear or branched alkyl, C 3- C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the ortho or meta substitution of the X substituent.
  • R 3 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, C 1 -C 3 alkanesulfonyl, said mono-substitution includes para, ortho or meta-substitution of triazolyl substitution on the benzene ring, and said multi-substitution Including two substitutions, three substitutions, and four substitutions.
  • More preferred compounds are the compounds represented by the general formula (IAa) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • More preferred compounds are the compounds represented by general formula (IAb) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • More preferred compounds are the compounds represented by general formula (IAc) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • More preferred compounds are the compounds represented by the general formula (IAd) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • More preferred compounds are the compounds represented by the general formula (IAe) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • More preferred compounds are the compounds represented by the general formula (IAf) and their physiologically acceptable salts:
  • X is selected from oxygen or sulfur atom; n is 1, 2, 3, 4 or 5; R 1 is a mono- or multi-substituted group on the benzene ring, selected from hydrogen, halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl; the mono-substitution includes the ortho or meta substitution of the X substituent, and the multi-substitution includes the X substituent Ortho-position disubstituted or other di-substituted, tri-substituted, tetra-substituted; R 2 is a mono- or poly-substituted group selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, trifluoromethyl, the mono-substitution includes the ortho- or meta-substitution of the nitrogen atom, and the poly-substitution includes
  • the halogens are each independently selected from F, Cl, Br, and I;
  • the C 1 -C 6 alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, tert-butyl;
  • the C 3 -C 6 cycloalkyl groups are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • the C 1 -C 3 Alkoxy groups are each independently selected from methoxy, ethoxy, propoxy, and isopropoxy.
  • the most preferred compounds are the following compounds and their physiologically acceptable salts, characterized in that the compounds are selected from:
  • the present invention provides the above-mentioned 1,2,4-triazole compounds.
  • the second aspect of the technical solution of the present invention is to provide a synthetic method of the compound of the first aspect, which includes the following steps:
  • n, X, Y, R 1 and Ar are as defined in any one of claims 1 to 10, and R 3 is methyl or ethyl.
  • the third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective dose of any 1,2,4-triazole compound described in the first aspect of the present invention And physiologically acceptable salts and pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems.
  • the compound of general formula I can be mixed with suitable pharmaceutical carrier materials, fragrances, flavors and pigments according to known methods, and made into tablets or coated tablets, or Suspend it with other additional substances or dissolve it in water or oil.
  • the compounds of the present invention can be administered orally or parenterally.
  • Oral medications can be tablets, capsules, coatings, and parenteral medications include injections and suppositories. These formulations are prepared according to methods well known to those skilled in the art.
  • the auxiliary materials used in the manufacture of tablets, capsules, and coatings are conventional auxiliary agents, such as starch, gelatin, acacia, silica, polyethylene glycol, and solvents used in liquid dosage forms such as water, ethanol, propylene glycol, and vegetable oil. Such as corn oil, peanut oil, olive oil, etc.
  • the preparations containing the compounds of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrating agents, preservatives, flavoring agents, pigments and the like.
  • the fourth aspect of the technical solution of the present invention is to provide the use of the 1,2,4-triazole compound and the physiologically acceptable salt thereof described in the first aspect in the preparation of xanthine oxidase inhibitors.
  • the fourth aspect of the technical solution of the present invention also provides the use of the 1,2,4-triazole compound and the physiologically acceptable salt thereof described in the first aspect in the preparation of a medicine for preventing or treating xanthine oxidase related diseases application.
  • the xanthine oxidase related diseases are selected from hyperuricemia and gout.
  • Xanthine oxidase inhibitors are the main uric acid-lowering drugs used clinically.
  • the compound of the present invention has a significant xanthine oxidase inhibitory effect.
  • the compound YDA-4-43 is more effective in reducing blood uric acid compared with the clinical similar product febuxostat, and its in vitro inhibitory XOD activity increases by about 1 order of magnitude (2.93nM vs 0.20nM); it is less effective for HUA models
  • the minimum effective oral dose for mice was reduced by 5 times (0.1mg/kg vs 0.5mg/kg).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) or high resolution mass spectrometry (HRMS).
  • NMR shift ( ⁇ ) is given in units of parts per million (ppm). mp is the melting point given in °C, without temperature correction.
  • Column chromatography generally uses 200-300 mesh silica gel as the carrier.
  • the NMR measurement was performed with INOVA-300, the measurement solvents were CDCl 3 , DMSO-D 6 , the internal standard was TMS, and the chemical shift was given in ppm.
  • the measurement of MS uses Agilent LC/MSD TOF LC/MS.
  • Example 2 The preparation method is similar to that of Example 1, except that 2,5-dimethyl-4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that 2-chloro-4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Embodiment 5 TAZ-3-5
  • Example 1 The preparation method is similar to that in Example 1, except that N-(2-chloroethyl)morpholine is used instead of N-(3-chloropropyl)morpholine in Example 1, and 4-cyanopyridine is used instead. 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to Example 1, except that methyl 4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4-cyanopyridine is used instead. 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to that in Example 1, except that methyl 3-methoxy-4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4 -Cyanopyridine replaces 3-cyanopyridine in Example 1.
  • the preparation method is similar to that of Example 1, using methyl 3-fluoro-4-hydroxybenzoate instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and using 4-cyanopyridine instead of Example 1.
  • the 3-cyanopyridine in 1.
  • Example 1 The preparation method is similar to that in Example 1, except that methyl 3-chloro-4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4-cyano Substituted 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to that in Example 1, except that methyl 3-bromo-4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4-cyano Substituted 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that methyl 4-hydroxy-3,5-dibromobenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1.
  • 4-cyanopyridine replaced 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to that in Example 1, except that methyl 3-trifluoromethyl-4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1. 4-cyanopyridine replaced 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to that of Example 1, except that methyl 3-iodo-4-hydroxybenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4-cyano Substituted 3-cyanopyridine in Example 1.
  • Example 16 The preparation method is similar to that in Example 16, except that N-(3-chloropropyl)pyrrole is used instead of N-(3-chloropropyl)piperidine in Example 1.
  • Example 16 The preparation method is similar to that in Example 16, except that 3-chloro-1-diethylaminopropane is used instead of N-(3-chloropropyl)piperidine in Example 1.
  • Example 16 The preparation method is similar to that in Example 16, except that 1-(3-chloropropyl)-4-methylpiperazine is used instead of N-(3-chloropropyl)piperidine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that the 3-cyanopyridine in Example 1 is replaced with 2-cyano-male.
  • Example 2 The preparation method is similar to that in Example 1, except that 4-bromobenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 2-fluorobenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 3-fluorobenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 4-chlorobenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 14.73(s,1H), 8.11–8.07(m,4H), 7.65–7.60(m,2H), 4.12(t,J 6.3Hz,2H), 3.63-3.54(m,4H), 2.57-2.48(m,2H), 2.39(s,4H), 2.00-1.91(m,2H).
  • Example 2 The preparation method is similar to that in Example 1, except that 4-methylbenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 4-methanesulfonyl benzonitrile is used instead of 3-cyanopyridine in Example 1.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 14.88(s,1H),8.33-8.24(m,2H),8.13-8.01(m,4H),4.08(t,J 6.3Hz,2H), 3.60--3.50(m,4H), 3.26(s,3H), 2.55-2.45(m,2H), 2.35(s,4H), 1.99-1.87(m,2H).
  • Example 2 The preparation method is similar to that in Example 1, except that 4-fluorobenzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 4-cyanoquinoline is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 2-cyanothiophene is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that 3-cyanothiophene is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 1-cyanonaphthalene is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to Example 1, except that benzonitrile is used instead of 3-cyanopyridine in Example 1.
  • Example 1 The preparation method is similar to Example 1, except that methyl 4-mercaptobenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1, and 4-cyanopyridine is used instead. 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that 2-bromo-4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that of Example 1, except that 2-cyanothiazole is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that 2-methyl-4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Example 2 The preparation method is similar to that in Example 1, except that 2-methoxy-4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Embodiment 41 YDA-4-43
  • Example 2 The preparation method is similar to that of Example 1, except that 4-cyanopyridine is used instead of 3-cyanopyridine in Example 1.
  • Embodiment 42 YDA-4-31
  • Example 2 The preparation method is similar to that of Example 1, except that 4-trifluoromethyl benzonitrile is used instead of 3-cyanopyridine in Example 1.
  • 1 H NMR 400MHz, CD 3 OD
  • Example 16 The preparation method is similar to that in Example 16, except that 2-fluorobenzonitrile is used instead of 4-cyanopyridine in Example 1.
  • Example 16 The preparation method is similar to that in Example 16, except that 4-trifluoromethyl benzonitrile is used instead of 4-cyanopyridine in Example 1.
  • Example 16 The preparation method is similar to that of Example 16, except that 4-cyanopyridine in Example 1 is replaced with 4-iodobenzonitrile.
  • Example 16 The preparation method is similar to that in Example 16, except that methyl 4-mercaptobenzoate is used instead of ethyl 4-hydroxy-3,5-dichlorobenzoate in Example 1.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 8.71–8.61(m,2H), 8.04–7.88(m,4H), 7.51–7.40(m,2H), 3.05(t,J 7.2Hz,2H ), 2.38-2.24 (m, 6H), 1.81-1.66 (m, 2H), 1.54--1.31 (m, 6H).
  • Example 16 The preparation method is similar to that in Example 16, except that N-(2-chloropropyl)butylamine is used instead of N-(3-chloropropyl)piperidine in Example 1.
  • the colorimetric method was used to determine the single-concentration inhibition rate of each compound on xanthine oxidase at a concentration of 10 ⁇ mol ⁇ L -1 . For compounds with a higher single-concentration inhibition rate, Further determine its half effective inhibitory concentration (IC 50 ) for xanthine oxidase.
  • the specific method is: dissolving the test sample in DMSO and configuring it into a 10mM stock solution. At 37°C and pH 7.4, 96-well plates were used to determine the effects of each compound on XOD-catalyzed xanthine (XAN) hydrolysis.
  • the reaction system contains 10 ⁇ mol ⁇ L -1 compound (final concentration), 3U/L XOD (not added in the control group, replaced by 0.01% DMSO), and buffer (3.5mM KH 2 PO 4 , 15.2mM K 2 HPO 4 , 0.25mM EDTA, and 50 ⁇ M XAN, pH 7.4).
  • a microplate reader was used to detect the luminosity of the product uric acid at a wavelength of 293nm to determine the XOD-catalyzed xanthine (XAN) hydrolysis, and the inhibition rate was calculated based on the OD value. Calculate the IC 50 value based on the OD value of multiple concentrations.
  • mice with steadily elevated blood uric acid levels were selected as hyperuricemia model mice.
  • Animals with high and stable blood uric acid levels were selected as hyperuricemia (HUA) model mice.
  • ICR mice weighing 24 to 26 g, were stimulated repeatedly with hypoxanthine combined with potassium oxazine, and animals with high and stable blood uric acid levels were selected as hyperuricemia (HUA) model mice.
  • the drug was administered once a day for 2 consecutive days, and blood uric acid level was determined by taking blood from the tail tip.
  • the same batch of normal ICR mice were given water by gavage as a normal control group. result:
  • the blood uric acid levels of the animals in each group are shown in Table 3. Compared with the normal control group, the blood uric acid level of the model control group animals was significantly increased. Compared with the model control group, the blood uric acid levels of the febuxostat group and the TAZ-3-16 group were significantly reduced.
  • Experimental example 4 The effect of the compound TAZ-3-19 of the present invention on reducing blood uric acid level in mice with acute hyperuricemia
  • ICR mice weighing 24 to 26 g, were stimulated by hypoxanthine combined with potassium oxazine to form an acute hyperuricemia mouse model.
  • the stomach was given water, the positive control drug febuxostat 5mg/kg, and the compound TAZ-3-190.625mg/kg, 1.25mg/kg, 2.5mg/kg.
  • the same batch of normal ICR mice were given water by gavage as a normal control group, and blood uric acid levels were measured by the tail-tip curve before administration and 1h, 2h, 4h after administration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于医药技术领域，具体公开了式(I)化合物所示的1,2,4-三唑类化合物，及其生理上可接受的盐，所述化合物的制备方法，含有所述化合物的药物制剂，以及所述化合物在制备预防和治疗与高尿酸血症相关疾病药物中的应用。

Description

1,2,4-三唑类化合物及其制法和药物用途 技术领域
本发明属于医药技术领域，具体涉及通式I所示的1,2,4-三唑类化合物，以及它们生理上可接受的盐；这些化合物的药物组合物、制备方法，以及这些化合物在制备黄嘌呤氧化酶抑制剂中的用途，在制备预防或治疗黄嘌呤氧化酶相关疾病的药物中的应用。
背景技术
高尿酸血症是一种因尿酸代谢障碍，导致血液中尿酸水平升高的疾病，极易引发痛风等其它代谢性疾病。统计显示，高尿酸血症及其引发的痛风已成为世界上仅次于糖尿病的第二大代谢性疾病。近年来，随着我国人们生活水平的提高，高尿酸血症和痛风的发病率也呈逐年上升趋势，给社会和家庭带来沉重负担。
人体内尿酸产生过多和尿酸排泄过少都有可能造成血尿酸水平增高，产生高尿酸血症。高水平血尿酸与很多疾病密切相关。首先是痛风，当体内尿酸水平超过其溶解限度时，尿酸盐出现结晶化，沉积在关节或软组织，引起炎症反应，继而诱发痛风。研究表明，超过21％的高尿酸血症患者最终发展为痛风。此外，高水平血尿酸还能够引起很多并发症。流行病学研究表明，高尿酸血症与很多疾病密切相关，如高血压、2型糖尿病、非酒精性脂肪肝病、肥胖症、慢性肾病、心血管疾病、中风等。
降低体内尿酸水平的主要途径包括抑制尿酸生成和促进尿酸排泄，因此，临床上使用的降尿酸药物主要分为两类，即抑制尿酸生成的黄嘌呤氧化酶(Xanthine oxidase,XO)抑制剂(别嘌呤醇、非布索坦、托匹司他等)及促进尿酸排泄的药物。而作为尿酸生成代谢途径中的关键酶，黄嘌呤氧化酶抑制剂在其中占据重要地位。
本发明旨在提供一种新的1,2,4-三唑类化合物，其具有高的黄嘌呤氧化酶抑制活性，可用于治疗高尿酸血症以及高尿酸血症引起的痛风等疾病。
发明内容
本发明的解决的技术问题是提供一种式I所示的新型1,2,4-三唑类化合物，其制备方法，药物组合物和在制备黄嘌呤氧化酶抑制剂中的用途，以及在制备预防或治疗与高尿酸血症有关的疾病中的用途。
为了解决本发明的技术问题，本发明采用如下技术方案：
本发明技术方案的第一方面是提供了一种由下述通式(I)表示的1,2,4-三唑类化合物及其生理上可接受的盐,
Figure PCTCN2020078082-appb-000001
其中，Ar选自取代或未取代的苯基、取代或未取代的吡啶基、嘧啶基、呋喃基、噻吩基、噻唑基、吲哚基、喹啉基、萘基，所述的取代基各自独立的选自卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基、C 1-C 3烷磺酰基；X选自氧或硫原子；n为1,2,3,4或5；Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基。
优选的化合物为通式(IA)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000002
其中，X选自氧或硫原子；n为1,2,3,4或5；Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基,所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
优选的化合物为通式(IB)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000003
其中，X选自氧或硫原子；n为1,2,3,4或5；Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6直链或支链烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 3为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基、C 1-C 3烷磺酰基，所述的单取代包括苯环上三唑基取代的对位、邻位或间位取代，所述的多取代包括二取代、三取代、四取代。
更优选的化合物为通式(IAa)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000004
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
更优选的化合物为通式(IAb)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000005
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
更优选的化合物为通式(IAc)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000006
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
更优选的化合物为通式(IAd)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000007
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、 四取代。
更优选的化合物为通式(IAe)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000008
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
更优选的化合物为通式(IAf)所示的化合物及其生理上可接受的盐：
Figure PCTCN2020078082-appb-000009
其中，X选自氧或硫原子；n为1,2,3,4或5；R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基；所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷 基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
以上通式中，所述的卤素各自独立的选自F、Cl、Br、I；所述的C 1-C 6烷基各自独立的选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基；所述的C 3-C 6环烷基各自独立的选自环丙基、环丁基、环戊基、环己基；所述的C 1-C 3烷氧基各自独立的选自甲氧基、乙氧基、丙氧基、异丙氧基。
最优选的化合物为下述的化合物及其生理上可接受的盐，其特征在于，所述的化合物选自：
Figure PCTCN2020078082-appb-000010
Figure PCTCN2020078082-appb-000011
Figure PCTCN2020078082-appb-000012
Figure PCTCN2020078082-appb-000013
Figure PCTCN2020078082-appb-000014
本发明提供上述的1,2,4-三唑类化合物，存在(I-1)、(I-2)、(I-3)三种异构体，统称为1,2,4-三唑，用通式(I)来表示。
异构体(I-1)
Figure PCTCN2020078082-appb-000015
异构体(I-2)
Figure PCTCN2020078082-appb-000016
异构体(I-3)
Figure PCTCN2020078082-appb-000017
本发明技术方案的第二方面是提供了第一方面所述化合物的合成方法，包括以下步骤：
式II化合物与卤代物反应生成的式III化合物，式III化合物肼解得到式IV化合物，式IV化合物与氰基化合物反应生成式I化合物：
Figure PCTCN2020078082-appb-000018
其中，n、X、Y、R 1及Ar的定义同权利要求1～10任一项所述，R 3为甲基或乙基。
本发明技术方案的第三方面是提供一种药物组合物，其特征在于，所述的药物组合物含有有效剂量的本发明第一方面所述的任一1,2,4-三唑类化合物及其生理上可接受的盐和在药学上可接受的载体或赋形 剂。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
为了制成药剂，可将通式I化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合，并被制成片剂或包衣的片剂，或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂，非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。
本发明技术方案的第四方面是提供了第一方面所述的1,2,4-三唑类化合物及其生理上可接受的盐在制备黄嘌呤氧化酶抑制剂中的用途。
本发明技术方案的第四方面还提供了第一方面所述的1,2,4-三唑类化合物及其生理上可接受的盐在制备预防或治疗黄嘌呤氧化酶相关疾病的药物中的应用。所述的黄嘌呤氧化酶相关疾病选自高尿酸血症、痛风。
药理学研究表明，本发明的通式I化合物具有抑制黄嘌呤氧化酶的活性，可有效降低体内的血尿酸水平，从而达到治疗的目的。
有益技术效果：
黄嘌呤氧化酶抑制剂是临床上使用的主要降尿酸药物。本发明涉及的化合物具有显著的黄嘌呤氧化酶抑制作用。其中，化合物YDA-4-43与临床同类产品非布索坦比较，降低血尿酸的药效更强，其体外抑制XOD活性增加了约1个数量级(2.93nM vs 0.20nM)；对HUA 模型小鼠的口服最低有效剂量降低了5倍(0.1mg/kg vs 0.5mg/kg)。
附图说明
图1.化合物TZA-3-19对急性高尿酸血症小鼠血尿酸水平的影响
具体实施方式
以下结合实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或质谱(MS)或高分辨质谱(HRMS)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。m.p.是以℃给出的熔点，温度未加校正。柱层析一般使用200～300目硅胶为载体。NMR测定是用INOVA-300，测定溶剂为CDCl 3、DMSO-D 6，内标为TMS，化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSD TOF液质联用仪。
实施例1：TAZ-3-1
Figure PCTCN2020078082-appb-000019
a)100mL圆底烧瓶中分别加入4-羟基-3,5-二氯苯甲酸乙酯(2.35g,10mmol)，N-(3-氯丙基)吗啉(1.96g,12mmol)，碳酸钾(2.76g,20mmol)，DMF(15mL)，80℃下反应12h，反应完成后蒸出大部分DMF，残余物加水溶解，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥备用。
b)100mL圆底烧瓶中依次加入上述产物,水合肼(80％N 2H 4, 5mL)，乙醇(20mL)，90℃下回流反应6h，溶液颜色由深变浅，反应后TLC检测，原料反应完全，蒸出乙醇和过量的水合肼，出现黄色固体，用混合溶剂(石油醚:乙酸乙酯＝1:1)洗,干燥备用。
c)在微波反应封管中依次加入3-氰基吡啶(156mg,1mmol)，4-异丁氧基-3-硝基苯甲酰肼(253mg,1mmol)，碳酸钾(276mg,2mmol)，正丁醇(3mL)，125℃下反应12h，反应后，蒸出溶剂，加水稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，柱层析分离(二氯甲烷:甲醇＝50:1)，得白色固体220mg，收率50.7％。 1H NMR(400MHz,DMSO-d 6)δ14.85(s,1H),9.25(d,J＝1.7Hz,1H),8.70(dd,J＝4.8,1.5Hz,1H),8.41(dt,J＝8.0,1.9Hz,1H),8.12(s,2H),7.58(dd,J＝7.9,4.8Hz,1H),4.12(t,J＝6.3Hz,2H),3.64–3.53(m,4H),2.58–2.46(m,2H),2.39(s,4H),2.06–1.77(m,2H).
实施例2：TAZ-3-2
Figure PCTCN2020078082-appb-000020
制备方法与实施例1类似，不同之处在于，用2,5-二甲基-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.87(s,1H),8.09(s,2H),7.66(s,2H),4.10(t,J＝6.3Hz,2H),3.65–3.53(m,4H),2.61–2.49(m,2H),2.38(s,4H),1.96(dd,J＝13.6,6.6Hz,2H).
实施例3：TAZ-3-3
Figure PCTCN2020078082-appb-000021
制备方法与实施例1类似，不同之处在于，用2-氯-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.96(s,1H),8.57(d,J＝5.1Hz,1H),8.13(s,2H),8.11–7.96(m,2H),4.12(t,J＝6.2Hz,2H),3.58(d,J＝4.3Hz,2H),2.52(dd,J＝12.9,4.3Hz,2H),2.40(s,4H),2.18–1.76(m,2H).
实施例4：TAZ-3-4
Figure PCTCN2020078082-appb-000022
制备方法与实施例1类似，不同之处在于，第一步用3-氯-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.97(s,1H),8.81(s,1H),8.66(d,J＝5.0Hz,1H),8.11(s,2H),8.00(d,J＝5.0Hz,1H),4.12(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.57–2.45(m,2H),2.38(s,4H),2.03–1.86(m,2H).
实施例5：TAZ-3-5
Figure PCTCN2020078082-appb-000023
制备方法与实施例1类似，不同之处在于，用2-氰基吡啶替代实 施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ15.01(s,1H),8.74(d,J＝4.5Hz,1H),8.19(d,J＝7.8Hz,1H),8.14–7.99(m,3H),7.64–7.50(m,1H),4.11(t,J＝6.2Hz,2H),3.58(d,J＝4.3Hz,4H),2.52(d,J＝11.9Hz,2H),2.38(s,4H),2.06–1.74(m,2H).
实施例6：TAZ-3-6
Figure PCTCN2020078082-appb-000024
制备方法与实施例1类似，不同之处在于，用N-(2-氯乙基)吗啉替代实施例1中的N-(3-氯丙基)吗啉，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.99(s,1H),8.75(d,J＝5.1Hz,2H),8.12(s,2H),8.09–7.98(m,2H),4.21(t,J＝5.6Hz,2H),3.59–3.46(m,4H),2.78(t,J＝5.6Hz,2H),2.56–2.34(m,4H).
实施例7：TAZ-3-7
Figure PCTCN2020078082-appb-000025
制备方法与实施例1类似，不同之处在于，用4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.64(s,1H),8.71(d,J＝5.9Hz,2H),8.05–7.96(m,4H),7.12(d,J＝8.8Hz,2H),4.09(t,J＝6.4Hz,2H),3.58(t,J＝4.5Hz,4H),2.47–2.31(m,4H),1.91(p,J ＝6.6Hz,2H).
实施例8：TAZ-3-8
Figure PCTCN2020078082-appb-000026
制备方法与实施例1类似，不同之处在于，用3-甲氧基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.64(s,1H),8.72(dd,J＝4.5,1.5Hz,2H),8.01(dd,J＝4.5,1.6Hz,2H),7.70–7.62(m,2H),7.15(d,J＝8.9Hz,1H),4.09(t,J＝6.4Hz,2H),3.88(s,2H),3.63–3.52(m,4H),2.43(dd,J＝19.6,12.5Hz,2H),1.92(dq,J＝13.5,6.6Hz,2H).
实施例9：TAZ-3-9
Figure PCTCN2020078082-appb-000027
制备方法与实施例1类似，用3-氟-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.74(s,1H),8.73(d,J＝5.9Hz,2H),8.00(dd,J＝4.5,1.6Hz,2H),7.88(dt,J＝7.3,2.5Hz,2H),7.38(t,J＝8.8Hz,1H),4.19(t,J＝6.4Hz,2H),3.63–3.52(m,4H),2.48–2.34(m,6H),2.02–1.73(m,2H).
实施例10：TAZ-3-10
Figure PCTCN2020078082-appb-000028
制备方法与实施例1类似，不同之处在于，用3-氯-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.73(s,1H),8.71(d,J＝5.4Hz,2H),8.10(d,J＝2.1Hz,1H),8.04–7.95(m,3H),7.34(d,J＝8.7Hz,1H),4.19(t,J＝6.3Hz,2H),3.61–3.51(m,4H),2.45(d,J＝7.0Hz,2H),2.37(s,4H),1.93(p,J＝6.6Hz,2H).
实施例11：TAZ-3-11
Figure PCTCN2020078082-appb-000029
制备方法与实施例1类似，不同之处在于，用3-溴-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.75(s,1H),8.73(dd,J＝4.5,1.5Hz,2H),8.29(d,J＝2.1Hz,1H),8.07(dd,J＝8.6,2.1Hz,1H),8.00(dd,J＝4.4,1.6Hz,2H),7.32(d,J＝8.7Hz,1H),4.20(t,J＝6.2Hz,2H),3.64–3.53(m,4H),2.54–2.44(m,2H),2.39(s,4H),2.01–1.83(m,2H).
实施例12：TAZ-3-12
Figure PCTCN2020078082-appb-000030
制备方法与实施例1类似，不同之处在于，用4-羟基-3,5-二溴苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.89(s,1H),8.75(d,J＝5.4Hz,2H),8.31(s,2H),8.01(d,J＝6.0Hz,2H),4.09(t,J＝6.3Hz,2H),3.60(d,J＝4.5Hz,2H),2.61–2.47(m,6H),2.42(s,4H),2.08–1.86(m,2H).
实施例13：TAZ-3-13
Figure PCTCN2020078082-appb-000031
制备方法与实施例1类似，不同之处在于，用3-甲基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.56(s,1H),8.69(dd,J＝4.5,1.5Hz,2H),7.98(dd,J＝4.5,1.6Hz,2H),7.91–7.84(m,2H),7.10(d,J＝9.2Hz,1H),4.09(t,J＝6.2Hz,2H),3.61–3.52(m,4H),2.46(t,J＝7.1Hz,2H),2.37(s,4H),2.23(s,3H),1.98–1.79(m,2H).
实施例14：TAZ-3-14
Figure PCTCN2020078082-appb-000032
制备方法与实施例1类似，不同之处在于，用3-三氟甲基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.82(s,1H),8.72(d,J＝5.6Hz,2H),8.30(d,J＝6.1Hz,2H),7.99(d,J＝5.9Hz,2H),7.46(d,J＝9.3Hz,1H),4.24(t,J＝6.0Hz,2H),3.63–3.50(m,4H),2.44(t,J＝7.0Hz,2H),2.35(s,4H),1.96–1.85(m,2H).
实施例15：TAZ-3-15
Figure PCTCN2020078082-appb-000033
制备方法与实施例1类似，不同之处在于，用3-碘-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.70(s,1H),8.71(d,J＝5.8Hz,2H),8.47(d,J＝1.9Hz,1H),8.06(dd,J＝8.6,1.9Hz,1H),7.98(d,J＝5.9Hz,2H),7.17(d,J＝8.7Hz,1H),4.16(t,J＝6.0Hz,2H),3.65–3.49(m,4H),2.53(s,2H),2.39(s,4H),1.93(dd,J＝13.7,7.1Hz,2H).
实施例16：TAZ-3-16
Figure PCTCN2020078082-appb-000034
a)100mL圆底烧瓶中分别加入4-羟基-3,5-二氯苯甲酸乙酯(2.35g,10mmol)，N-(3-氯丙基)哌啶(1.93g,12mmol)，碳酸钾(2.76g,20mmol)，DMF(15mL)，80℃下反应12h，反应完成后蒸出大部分DMF，残余物加水溶解，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥备用。
b)100mL圆底烧瓶中依次加入上述产物,水合肼(80％N 2H 4,5mL)，乙醇(20mL)，90℃下回流反应6h，溶液颜色由深变浅，反应后TLC检测，原料反应完全，蒸出乙醇和过量的水合肼，出现黄色固体，用混合溶剂(石油醚:乙酸乙酯＝1:1)洗,干燥备用。
c)在微波反应封管中依次加入4-氰基吡啶(156mg,1mmol)，取代的苯甲酰肼(345mg,1mmol)，碳酸钾(276mg,2mmol)，正丁醇(3mL)，125℃下反应12h，反应后，蒸出溶剂，加水稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，柱层析分离(二氯甲烷:甲醇＝50:1)，得黄色固体254mg，收率58.8％。 1H NMR(400MHz,DMSO-d 6)δ8.72(dd,J＝4.5,1.6Hz,2H),8.11(s,2H),7.98(dd,J＝4.5,1.6Hz,2H),4.09(t,J＝6.3Hz,2H),2.52–2.45(m,2H),2.36(s,4H),1.99–1.86(m,2H),1.54–1.43(m,4H),1.38(d,J＝5.3Hz,2H).
实施例17：TAZ-3-17
Figure PCTCN2020078082-appb-000035
制备方法与实施例16类似，不同之处在于，用N-(3-氯丙基)吡咯替代实施例1中的N-(3-氯丙基)哌啶。 1H NMR(400MHz,DMSO-d 6)δ8.73(dd,J＝4.5,1.5Hz,2H),8.15–8.09(m,2H),8.00(dd,J＝4.5,1.6Hz,2H),4.12(t,J＝6.3Hz,2H),2.72(t,J＝7.3Hz,2H),2.55(d,J＝6.4Hz,2H),2.50(dt,J＝3.6,1.8Hz,1H),2.06–1.94(m,2H),1.91(s,1H),1.76–1.68(m,4H).
实施例18：TAZ-3-18
Figure PCTCN2020078082-appb-000036
制备方法与实施例16类似，不同之处在于，用3-氯-1-二乙氨基丙烷替代实施例1中的N-(3-氯丙基)哌啶。 1H NMR(400MHz,DMSO-d 6)δ8.74(d,J＝5.9Hz,2H),8.14(s,2H),8.01(dd,J＝4.5,1.6Hz,2H),4.12(t,J＝6.2Hz,2H),2.80–2.69(m,2H),2.62(q,J＝7.1Hz,4H),2.02–1.87(m,4H),1.02(t,J＝7.1Hz,6H).
实施例19：TAZ-3-19
Figure PCTCN2020078082-appb-000037
制备方法与实施例16类似，不同之处在于，用1-(3-氯丙基)-4-甲基哌嗪替代实施例1中的N-(3-氯丙基)哌啶。 1H NMR(400MHz,DMSO-d 6)δ8.74(dd,J＝4.5,1.6Hz,2H),8.13(s,2H),8.00(dd,J＝4.5,1.6Hz,2H),4.11(t,J＝6.3Hz,2H),2.55–2.47(m,4H),2.44–2.27(m,6H),2.16(s,3H),2.01–1.88(m,2H).
实施例20：TAZ-3-20
Figure PCTCN2020078082-appb-000038
制备方法与实施例1类似，不同之处在于，用2-氰基妇男替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.07(s,2H),7.92(dd,J＝1.9,0.6Hz,1H),7.12(d,J＝4.1Hz,1H),6.72(dd,J＝3.6,1.9Hz,1H),4.17–4.05(m,2H),3.64–3.53(m,4H),2.53(d,J＝7.9Hz,2H),2.38(d,J＝4.5Hz,4H),1.96(t,J＝7.2Hz,2H).
实施例21：TAZ-3-21
Figure PCTCN2020078082-appb-000039
制备方法与实施例1类似，不同之处在于，用5-氰基吲哚替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.45(s,1H),11.38(s,1H),8.32(s,1H),8.14–8.08(m,1H),7.97(s,1H),7.84(dd,J＝8.5,1.6Hz,1H),7.55(d,J＝8.5Hz,1H),7.46(t,J＝2.7Hz,1H),6.58(s,1H),4.15–4.03(m,2H),3.58(dd,J＝9.5,5.3Hz,4H),2.56–2.47(m,2H),2.39(s,4H),2.01–1.89(m,2H).
实施例22：TAZ-3-22
Figure PCTCN2020078082-appb-000040
制备方法与实施例1类似，不同之处在于，用4-溴苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.74(s,1H),8.10(s,2H),8.02(d,J＝8.5Hz,2H),7.76(d,J＝8.4Hz,2H),4.12(t,J＝6.2Hz,2H),3.65–3.54(m,4H),2.56–2.44(m,2H),2.39(s,4H),2.07–1.82(m,2H).
实施例23：TAZ-3-23
Figure PCTCN2020078082-appb-000041
制备方法与实施例1类似，不同之处在于，用2-氟苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.60(s,1H),8.66(s,1H),8.16–8.06(m,3H),7.98(s,1H),7.65–7.54(m,1H),7.49–7.36(m,2H),4.12(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.58–2.44(m,2H),2.39(s,4H),2.04–1.89(m,2H).
实施例24：TAZ-3-24
Figure PCTCN2020078082-appb-000042
制备方法与实施例1类似，不同之处在于，用3-氟苯腈替代实施 例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.77(s,1H),8.12(s,2H),7.96–7.91(m,1H),7.85(ddd,J＝10.0,2.5,1.5Hz,1H),7.61(td,J＝8.1,6.1Hz,1H),7.36(td,J＝8.3,2.2Hz,1H),4.13(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.58–2.48(m,2H),2.39(s,4H),2.02–1.89(m,2H).
实施例25：TAZ-3-25
Figure PCTCN2020078082-appb-000043
制备方法与实施例1类似，不同之处在于，用4-氯苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.73(s,1H),8.11–8.07(m,4H),7.65–7.60(m,2H),4.12(t,J＝6.3Hz,2H),3.63–3.54(m,4H),2.57–2.48(m,2H),2.39(s,4H),2.00–1.91(m,2H).
实施例26：TAZ-3-26
Figure PCTCN2020078082-appb-000044
制备方法与实施例1类似，不同之处在于，用4-甲基苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.59(s,1H),8.09(s,2H),7.97(d,J＝8.1Hz,2H),7.37(d,J＝8.2Hz,2H),4.11(t,J＝6.3Hz,2H),3.63–3.54(m,4H),2.57–2.46(m,2H),2.39(s,7H),1.96(p,J＝6.5Hz,2H).
实施例27：TAZ-3-27
Figure PCTCN2020078082-appb-000045
制备方法与实施例1类似，不同之处在于，用4-甲磺酰基苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.88(s,1H),8.33–8.24(m,2H),8.13–8.01(m,4H),4.08(t,J＝6.3Hz,2H),3.60–3.50(m,4H),3.26(s,3H),2.55–2.45(m,2H),2.35(s,4H),1.99–1.87(m,2H).
实施例28：TAZ-3-28
Figure PCTCN2020078082-appb-000046
制备方法与实施例1类似，不同之处在于，用4-氟苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.67(s,1H),8.16–8.02(m,4H),7.39(t,J＝8.8Hz,2H),4.11(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.56–2.47(m,2H),2.39(s,4H),1.96(p,J＝6.6Hz,2H).
实施例29：TAZ-3-29
Figure PCTCN2020078082-appb-000047
制备方法与实施例1类似，不同之处在于，用4-氰基喹啉替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.99(s,1H),9.17(d,J＝8.3Hz,1H),9.05(d,J＝4.5Hz,1H),8.19(s,2H),8.15–8.08(m,2H),7.85(ddd,J＝8.4,6.9,1.4Hz,1H),7.76(ddd,J＝8.3,6.8,1.3Hz,1H),4.13(t,J＝6.3Hz,2H),3.61–3.52(m,4H),2.58–2.46(m,2H),2.39(s,4H),2.04–1.90(m,2H).
实施例30：TAZ-3-30
Figure PCTCN2020078082-appb-000048
制备方法与实施例1类似，不同之处在于，用2-氰基噻吩替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.61(s,1H),8.02(s,2H),7.71(d,J＝4.3Hz,2H),7.23–7.15(m,1H),4.07(t,J＝6.3Hz,2H),3.58–3.50(m,4H),2.54–2.44(m,2H),2.35(s,4H),1.99–1.82(m,2H).
实施例31：TAZ-3-31
Figure PCTCN2020078082-appb-000049
制备方法与实施例1类似，不同之处在于，用3-氰基噻吩替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.54(s,1H),8.18(dd,J＝2.9,1.1Hz,1H),8.11–7.98(m,2H),7.74(dd,J＝5.0,2.9 Hz,1H),7.66(dd,J＝5.0,1.2Hz,1H),4.09(t,J＝6.3Hz,2H),3.61–3.51(m,4H),2.55–2.46(m,2H),2.37(s,4H),2.01–1.87(m,2H).
实施例32：TAZ-3-32
Figure PCTCN2020078082-appb-000050
制备方法与实施例1类似，不同之处在于，用1-氰基萘替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.78(s,1H),8.68(s,1H),8.23–8.06(m,5H),8.06–7.94(m,1H),7.68–7.57(m,2H),4.13(t,J＝6.3Hz,2H),3.64–3.53(m,4H),2.58–2.47(m,2H),2.39(s,4H),2.04–1.84(m,2H).
实施例33：TAZ-3-33
Figure PCTCN2020078082-appb-000051
制备方法与实施例1类似，不同之处在于，用苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.67(s,1H),8.11–8.03(m,3H),7.96(s,1H),7.59–7.45(m,3H),4.10(t,J＝6.3Hz,2H),3.61–3.50(m,4H),2.55–2.46(m,2H),2.37(s,4H),2.01–1.85(m,2H).
实施例34：TAZ-3-34
Figure PCTCN2020078082-appb-000052
制备方法与实施例1类似，不同之处在于，用4-巯基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.74–8.68(m,2H),7.99(ddd,J＝7.4,5.4,2.0Hz,4H),7.48(dd,J＝6.5,4.4Hz,2H),3.64–3.48(m,4H),3.08(t,J＝7.4Hz,1H),2.56–2.45(m,4H),2.39(t,J＝7.1Hz,1H),2.36–2.22(m,3H),1.76(t,J＝7.4Hz,1H).
实施例35：TAZ-3-35
Figure PCTCN2020078082-appb-000053
制备方法与实施例1类似，不同之处在于，用2-氟-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.99(s,1H),8.40(d,J＝5.2Hz,1H),8.13(d,J＝3.1Hz,2H),7.95(dt,J＝5.2,1.5Hz,1H),7.69(s,1H),4.11(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.56–2.47(m,2H),2.38(s,4H),2.02–1.85(m,2H).
实施例36：TAZ-3-36
Figure PCTCN2020078082-appb-000054
制备方法与实施例1类似，不同之处在于，用2-溴-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.99(s,1H),8.51(d,J＝5.0Hz,1H),8.13(d,J＝0.4Hz,1H),8.08(s,2H),7.99(dd,J＝5.1,1.3Hz,1H),4.08(t,J＝6.3Hz,2H),3.63–3.48(m,4H),2.58–2.45(m,2H),2.36(s,4H),2.05–1.75(m,2H).
实施例37：TAZ-3-37
Figure PCTCN2020078082-appb-000055
制备方法与实施例1类似，不同之处在于，用2-氰基噻唑替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ15.16(s,1H),8.09–8.04(m,2H),7.98(d,J＝3.2Hz,1H),4.11(t,J＝6.3Hz,2H),3.60–3.51(m,4H),2.56–2.46(m,2H),2.38(s,4H),2.03–1.86(m,2H).
实施例38：TAZ-3-38
Figure PCTCN2020078082-appb-000056
制备方法与实施例1类似，不同之处在于，用2-甲基-4-氰基吡啶 替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.61(d,J＝5.2Hz,1H),8.12(s,2H),7.89(s,1H),7.83–7.77(m,1H),4.12(t,J＝6.3Hz,2H),3.66–3.54(m,4H),2.58(s,3H),2.56–2.50(m,2H),2.40(s,4H),1.97(p,J＝6.5Hz,2H).
实施例39：TAZ-3-39
Figure PCTCN2020078082-appb-000057
制备方法与实施例1类似，不同之处在于，用2-甲氧基-4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.33(dd,J＝5.3,0.7Hz,1H),8.11(s,2H),7.61(dd,J＝5.3,1.4Hz,1H),7.40(dd,J＝1.3,0.7Hz,1H),4.12(t,J＝6.3Hz,2H),3.93(s,3H),3.62–3.54(m,4H),2.56–2.48(m,6H),2.03–1.89(m,2H).
实施例40：TAZ-3-40
Figure PCTCN2020078082-appb-000058
制备方法与实施例1类似，不同之处在于，用2-氰基嘧啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ15.21(s,1H),9.01(d,J＝4.9Hz,2H),8.09(s,2H),7.64(t,J＝4.9Hz,1H),4.10(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.56–2.46(m,2H),2.38(s,4H),2.03–1.87(m,2H).
实施例41：YDA-4-43
Figure PCTCN2020078082-appb-000059
制备方法与实施例1类似，不同之处在于，用4-氰基吡啶替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ14.97(s,1H),8.76(d,J＝5.9Hz,2H),8.14(s,2H),8.01(dd,J＝4.6,1.5Hz,2H),4.13(t,J＝6.3Hz,2H),3.67–3.48(m,4H),2.58–2.49(m,2H),2.40(s,4H),1.98(p,J＝6.6Hz,2H).
实施例42：YDA-4-31
Figure PCTCN2020078082-appb-000060
制备方法与实施例1类似，不同之处在于，用4-三氟甲基苯腈替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,CD 3OD)δ8.25(d,J＝7.6Hz,2H),8.10(s,2H),7.82(d,J＝7.6Hz,2H),4.16(t,J＝5.6Hz,2H),3.72(m,4H),2.79–2.63(m,2H),2.55(s,4H),2.12–2.07(m,2H).
实施例43：TAZ-3-48
Figure PCTCN2020078082-appb-000061
制备方法与实施例16类似，不同之处在于，用2-氟苯腈替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ7.89(s,2H),7.76–7.64(m,2H),7.54–7.37(m,2H),4.10(t,J＝6.9Hz,2H),2.24(s,6H),1.97(t,J＝6.9Hz,2H),1.34(s,6H).
实施例44：TAZ-3-49
Figure PCTCN2020078082-appb-000062
制备方法与实施例16类似，不同之处在于，用3-氟苯腈替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.10(s,2H),7.93(dt,J＝7.8,1.2Hz,1H),7.84(ddd,J＝10.0,2.6,1.5Hz,1H),7.59(td,J＝8.1,6.0Hz,1H),7.35(tdd,J＝8.4,2.7,1.0Hz,1H),4.10(t,J＝6.3Hz,2H),2.52(m,2H),2.39(s,4H),2.00–1.88(m,2H),1.56–1.37(m,6H).
实施例45：TAZ-3-51
Figure PCTCN2020078082-appb-000063
制备方法与实施例16类似，不同之处在于，用4-三氟甲基苯腈替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.29(d,J＝8.1Hz,2H),8.12(s,2H),7.91(d,J＝8.4Hz,2H),4.10(t,J＝6.3Hz, 2H),2.49(m,2H),2.37(s,4H),1.95(p,J＝6.6Hz,2H),1.57–1.36(m,6H).
实施例46：TAZ-3-58
Figure PCTCN2020078082-appb-000064
制备方法与实施例16类似，不同之处在于，用4-碘苯腈替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ7.88-7.77(m,4H),7.70(s,2H),4.28(t,J＝6.8Hz,2H),2.49(s,6H),2.15-2.02(m,2H),1.47-1.37(m,6H).
实施例47：TAZ-3-60
Figure PCTCN2020078082-appb-000065
制备方法与实施例16类似，用3-氰基吡啶替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ9.25(d,J＝2.3Hz,1H),8.69(dd,J＝4.8,1.7Hz,1H),8.45–8.38(m,1H),8.12(s,2H),7.58(dd,J＝8.0,4.8Hz,1H),4.11(t,J＝6.3Hz,2H),2.54(m,2H),2.40(s,4H),1.96(t,J＝6.9Hz,2H),1.52–1.32(m,6H).
实施例48：TAZ-3-61
Figure PCTCN2020078082-appb-000066
制备方法与实施例16类似，不同之处在于，用2-氰基吡啶替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.78–8.66(m,1H),8.19(d,J＝7.9Hz,1H),8.09(s,2H),8.03(td,J＝7.7,1.7Hz,1H),7.57(ddd,J＝7.6,4.8,1.3Hz,1H),4.10(t,J＝6.3Hz,2H),2.40(m,6H),1.96(t,J＝6.9Hz,2H),1.54–1.37(m,6H).
实施例49：TAZ-3-62
Figure PCTCN2020078082-appb-000067
制备方法与实施例16类似，不同之处在于，用2-氰基呋喃替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.06(s,2H),7.91(d,J＝1.8Hz,1H),7.11(d,J＝3.4Hz,1H),6.71(dd,J＝3.5,1.8Hz,1H),4.10(t,J＝6.3Hz,2H),2.41(m,6H),2.04–1.88(m,2H),1.55–1.39(m,6H).1H),7.11(d,J＝3.4Hz,1H),6.71(dd,J＝3.5,1.8Hz,1H),4.10(t,J＝6.3Hz,2H),2.41(m,6H),2.04–1.88(m,2H),1.55–1.39(m,6H).
实施例50：TAZ-3-63
Figure PCTCN2020078082-appb-000068
制备方法与实施例16类似，不同之处在于，用2-甲基4-氰基吡啶 替代实施例1中的3-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.60(d,J＝5.2Hz,1H),8.12(s,2H),7.88(s,1H),7.79(dd,J＝5.1,1.6Hz,1H),4.11(t,J＝6.3Hz,2H),2.51(s,3H),2.42(m,6H),1.97(t,J＝6.9Hz,2H),1.57–1.34(m,6H).
实施例51：TAZ-3-64
Figure PCTCN2020078082-appb-000069
制备方法与实施例16类似，不同之处在于，用2-氟4-氰基吡啶替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.40(d,J＝5.2Hz,1H),8.16(s,2H),7.97(ddd,J＝5.2,2.0,1.2Hz,1H),7.71(d,J＝1.7Hz,1H),4.13(t,J＝6.1Hz,2H),2.88–2.63(m,6H),2.16–2.02(m,2H),1.68–1.40(m,6H).
实施例52：TAZ-3-65
Figure PCTCN2020078082-appb-000070
制备方法与实施例16类似，不同之处在于，用2-氯4-氰基吡啶替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.55(d,J＝5.1Hz,1H),8.13(s,2H),8.04(t,J＝1.0Hz,1H),8.00(dd,J＝5.1,1.4Hz,1H),4.11(t,J＝6.2Hz,2H),2.64(t,J＝7.3Hz,2H),2.49(m,4H),2.06–1.94(m,2H),1.58–1.34(m,6H).
实施例53：TAZ-3-66
Figure PCTCN2020078082-appb-000071
制备方法与实施例16类似，不同之处在于，用2-溴4-氰基吡啶替代实施例1中的4-氰基吡啶。 1H NMR(400MHz,DMSO-d 6)δ8.54(dd,J＝5.1,0.7Hz,1H),8.18(dd,J＝1.5,0.7Hz,1H),8.14(s,2H),8.03(dd,J＝5.1,1.4Hz,1H),4.12(t,J＝6.2Hz,2H),2.72(t,J＝7.4Hz,2H),2.60(s,4H),2.03(t,J＝7.3Hz,2H),1.62–1.38(m,6H).
实施例54：TAZ-3-69
Figure PCTCN2020078082-appb-000072
制备方法与实施例16类似，不同之处在于，用3-氟-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz,DMSO-d 6)δ8.76–8.63(m,2H),8.04–7.93(m,2H),7.92–7.80(m,2H),7.36(t,J＝8.8Hz,1H),4.16(t,J＝6.4Hz,2H),2.37(dt,J＝24.4,6.6Hz,6H),1.97–1.83(m,2H),1.54–1.29(m,6H).
实施例55：TAZ-3-70
Figure PCTCN2020078082-appb-000073
制备方法与实施例16类似，不同之处在于，用3-氯-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz, DMSO-d 6)δ8.73–8.65(m,2H),8.11(d,J＝2.1Hz,1H),8.02–7.94(m,3H),7.34(d,J＝8.7Hz,1H),4.18(t,J＝6.4Hz,2H),2.47–2.24(m,6H),1.98–1.87(m,2H),1.55–1.32(m,6H).
实施例56：TAZ-3-71
Figure PCTCN2020078082-appb-000074
制备方法与实施例16类似，不同之处在于，用3-溴-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz,DMSO-d 6)δ8.76–8.68(m,2H),8.27(d,J＝2.1Hz,1H),8.11–7.95(m,3H),7.30(d,J＝8.7Hz,1H),4.17(q,J＝6.6Hz,2H),2.47–2.25(m,6H),1.91(h,J＝6.4Hz,2H),1.56–1.30(m,6H).
实施例57：TAZ-3-72
Figure PCTCN2020078082-appb-000075
制备方法与实施例16类似，不同之处在于，用3-碘-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz,DMSO-d 6)δ8.74–8.67(m,2H),8.47(d,J＝2.1Hz,1H),8.06(dd,J＝8.6,2.1Hz,1H),8.03–7.96(m,2H),7.18(d,J＝8.7Hz,1H),4.15(t,J＝6.1Hz,2H),2.49–2.30(m,6H),1.91(t,J＝6.7Hz,2H),1.56–1.31(m,6H).
实施例58：TAZ-3-74
Figure PCTCN2020078082-appb-000076
制备方法与实施例16类似，不同之处在于，用3-三氟甲基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz,DMSO-d 6)δ8.76–8.64(m,2H),8.30(dd,J＝4.7,2.5Hz,2H),8.04–7.89(m,2H),7.46(d,J＝9.3Hz,1H),4.22(t,J＝6.0Hz,2H),2.43–2.28(m,6H),1.90(t,J＝6.7Hz,2H),1.52–1.32(m,6H).
实施例59：TAZ-3-75
Figure PCTCN2020078082-appb-000077
制备方法与实施例16类似，不同之处在于，用4-巯基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯。 1H NMR(400MHz,DMSO-d 6)δ8.71–8.61(m,2H),8.04–7.88(m,4H),7.51–7.40(m,2H),3.05(t,J＝7.2Hz,2H),2.38–2.24(m,6H),1.81–1.66(m,2H),1.54–1.31(m,6H).
实施例60：TAZ-3-79
Figure PCTCN2020078082-appb-000078
制备方法与实施例16类似，不同之处在于，用N-(2-氯丙基)吡咯替代实施例1中的N-(3-氯丙基)哌啶。 1H NMR(400MHz,DMSO-d 6)δ 8.80–8.73(m,1H),8.68–8.61(m,1H),7.96–7.87(m,1H),7.86–7.78(m,1H),7.60(s,1H),7.47(s,1H),4.29(q,J＝6.6Hz,2H),2.79(t,J＝6.5Hz,1H),2.67(t,J＝6.1Hz,1H),2.35(s,2H),2.22(s,2H),1.54–1.22(m,6H).
实施例61：TAZ-3-80
Figure PCTCN2020078082-appb-000079
制备方法与实施例16类似，不同之处在于，用N-(2-氯丙基)丁胺替代实施例1中的N-(3-氯丙基)哌啶。 1H NMR(400MHz,DMSO-d 6)δ8.72–8.65(m,2H),7.97–7.87(m,2H),7.67(s,2H),4.34(t,J＝6.8Hz,2H),2.59–2.40(m,4H),2.06(t,J＝7.0Hz,2H),1.39–1.11(m,10H),0.82(td,J＝7.2,3.0Hz,6H).
药理实验
实验例1：本发明的化合物对黄嘌呤氧化酶的抑制作用
方法：
采用非布索坦与托匹司他作为阳性对照，利用比色法测定各化合物在10μmol·L -1浓度下对黄嘌呤氧化酶的单浓度抑制率，对于单浓度抑制率较高的化合物，进一步测定其对黄嘌呤氧化酶的半数有效抑制浓度(IC 50)。
具体方法为：将测试样品溶解于DMSO中，配置成10mM储备液。在37℃、pH7.4下，采用96孔板测定各化合物对XOD-催化黄嘌呤(XAN)水解作用的影响。反应体系中含10μmol·L -1的化合物(终浓度)，3U/L XOD(对照组不加，以0.01％DMSO代替)，及缓冲液(3.5mM KH 2PO 4, 15.2mM K 2HPO 4,0.25mM EDTA,及50μM XAN,pH 7.4)。采用酶标仪检测293nm波长下产物尿酸的光度，来测定XOD-催化的黄嘌呤(XAN)水解作用，依据OD值计算抑制率。根据多个浓度的OD值计算IC 50值。
结果：
分别测定了上述化合物在终浓度为10 -5μmol·L -1时对黄嘌呤氧化酶的抑制率；测定并计算几种本发明化合物的IC 50值。结果如表1所示。
表1.化合物对黄嘌呤氧化酶的抑制作用
Figure PCTCN2020078082-appb-000080
Figure PCTCN2020078082-appb-000081
ND：未测定。
实验例2：本发明化合物YDA-4-43对高尿酸血症小鼠的体内降尿酸作用
方法：
采用次黄嘌呤联合氧嗪酸钾连续多次刺激的方法，挑选血尿酸水平稳定升高的动物作为高尿酸血症模型小鼠。选择血尿酸水平高且稳定的动物作为高尿酸血症(HUA)模型小鼠。将HUA小鼠按血尿酸水平随机分5组(n＝8)，分别为模型对照、非布索坦、不同剂量YDA-4-43组，分别灌胃给予水、阳性药非布索坦0.5mg/kg和化合物YDA-4-43 0.1，0.5，2.5mg/kg，每天给药1次，连续给药2天。同时，设同批ICR小鼠作为正常对照组(n-＝8)，灌胃给予同体积水。监测动物血尿酸水平。结果：
连续给药2天后，各组动物血尿酸水平如表2所示。口服化合物YDA-4-43在0.1，0.5，2.5mg/kg均可显著降低HUA小鼠的血尿酸水平。化合物YDA-4-43降低HUA小鼠血尿酸水平的作用与阳性对照药非布索坦类似。
表2.化合物YDA-4-43对HUA高尿酸血症小鼠的降低血尿酸作用
Figure PCTCN2020078082-appb-000082
Figure PCTCN2020078082-appb-000083
***，p<0.001vs正常对照组；#，##，###，p<0.05,0.01，0.001vs模型对照组
实验例3：本发明化合物TAZ-3-16对高尿酸血症小鼠降低血尿酸水平的作用
方法：
ICR小鼠，体重24～26g，采用次黄嘌呤联合氧嗪酸钾连续多次刺激的方法，选择血尿酸水平高且稳定的动物作为高尿酸血症(HUA)模型小鼠。将模型小鼠随机分为3组(n＝10)：模型对照、非布索坦、和化合物TAZ-3-16组，分别灌胃给予水、阳性对照药非布索坦1mg/kg、和化合物TAZ-3-16 0.5mg/kg。每天给药1次，连续给药2天，经尾尖取血测定血尿酸水平。同批正常ICR小鼠灌胃给予水作为正常对照组。结果：
各组动物血尿酸水平如表3所示。与正常对照组比较，模型对照组动物的血尿酸水平明显升高。与模型对照组比较，非布索坦组、TAZ-3-16组的血尿酸水平均明显降低。
表3.化合物TZA-3-16对HUA模型小鼠的降低血尿酸作用。
Figure PCTCN2020078082-appb-000084
***，p<0.001vs正常对照组；###，p<0.001vs模型对照组
实验例4：本发明化合物TAZ-3-19对急性高尿酸血症小鼠的降低血尿酸水平作用
方法：
ICR小鼠，体重24～26g，采用次黄嘌呤联合氧嗪酸钾刺激的方法，形成急性高尿酸血症小鼠模型。将模型小鼠随机分为5组(n＝10)：模型、非布索坦、和化合物TAZ-3-19-0.625、TAZ-3-19-1.25、TAZ-3-19-2.5，分别灌胃给予水、阳性对照药非布索坦5mg/kg、和化合物TAZ-3-190.625mg/kg、1.25mg/kg、2.5mg/kg。同批正常ICR小鼠灌胃给予水作为正常对照组，分别于给药前、给药后1h、2h、4h经尾尖曲线测定血尿酸水平。
结果：
与正常对照组比较，模型对照组动物的血尿酸水平明显升高。与模型对照组比较，TAZ-3-19-0.625、TAZ-3-19-1.25和TAZ-3-19-2.5组的血尿酸峰值分别降低了5.7％、34.2％和68.0％(图1，表4)。
表4.化合物TZA-3-19降低急性高尿酸血症模型小鼠血尿酸水平的作用
Figure PCTCN2020078082-appb-000085
***，p<0.001vs正常对照组；###，p<0.001vs模型对照组。

Claims (17)

  1. 一种由下述通式(I)表示的1,2,4-三唑类化合物及其生理上可接受的盐，
    Figure PCTCN2020078082-appb-100001
    其中，
    Ar选自取代或未取代的苯基、取代或未取代的吡啶基、嘧啶基、呋喃基、噻吩基、噻唑基、吲哚基、喹啉基、萘基，所述的取代基为苯基或吡啶基上的单取代或多取代基团，其各自独立的选自卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基、C 1-C 3烷磺酰基；
    X选自氧或硫原子；
    n为1,2,3,4或5；
    Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基。
  2. 根据权利要求1所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IA)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100002
    Figure PCTCN2020078082-appb-100003
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
  3. 根据权利要求1所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IB)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100004
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    Y选自C 1-C 6烷基取代的胺基、C 3-C 6环烷基取代的胺基、吡咯基、哌啶基、哌嗪基以及吗啉基；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 3为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基、C 1-C 3烷磺酰基，所述的单取代包括苯环上三唑基取代的对位、邻位或间位取代，所述的多取代包括二取代、三取代、四取代。
  4. 根据权利要求2所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAa)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100005
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、 四取代。
  5. 根据权利要求1所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAb)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100006
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
  6. 根据权利要求2所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAc)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100007
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
  7. 根据权利要求2所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAd)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100008
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
  8. 根据权利要求2所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAe)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100009
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、 四取代。
  9. 根据权利要求2所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物是通式(IAf)所示的化合物及其生理上可接受的盐：
    Figure PCTCN2020078082-appb-100010
    其中，
    X选自氧或硫原子；
    n为1,2,3,4或5；
    R 1为苯环上的单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括X取代基的邻位或间位取代，所述的多取代包括X取代基的邻位二取代或其它二取代、三取代、四取代；
    R 2为单取代或多取代基团，选自氢、卤素、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基、三氟甲基，所述的单取代包括氮原子的邻位或间位取代，所述的多取代包括氮原子的邻位二取代或其它二取代、三取代、四取代。
  10. 根据权利要求1-9任一项所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的卤素各自独立地选自F、Cl、Br、I；所述的C 1-C 6烷基各自独立地选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基；所述的C 3-C 6环烷基各自独立的选自环丙基、环丁基、环戊基、环己基；所述的C 1-C 3烷氧基各自独立地选自甲氧基、 乙氧基、丙氧基、异丙氧基。
  11. 根据权利要求1所述的1,2,4-三唑类化合物及其生理上可接受的盐，其特征在于，所述的化合物选自：
    Figure PCTCN2020078082-appb-100011
    Figure PCTCN2020078082-appb-100012
    Figure PCTCN2020078082-appb-100013
    Figure PCTCN2020078082-appb-100014
    Figure PCTCN2020078082-appb-100015
  12. 权利要求1～11任一项所述1,2,4-三唑类化合物的制备方法，其特征在于，包括以下步骤：
    式II化合物与卤代物反应生成的式III化合物，式III化合物肼解得到式IV化合物，式IV化合物与氰基化合物反应生成式I化合物：
    Figure PCTCN2020078082-appb-100016
    其中，n、X、Y、R 1及Ar的定义同权利要求1～11任一项所述，R 4为甲基或乙基。
  13. 一种药物组合物，其特征在于，所述的药物组合物含有有效剂量的如权利要求1～11任一项所述的任一1,2,4-三唑类化合物及其生理上可接受的盐和在药学上可接受的载体或赋形剂。
  14. 根据权利要求13所述的药物组合物，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
  15. 权利要求1～11任一项所述的1,2,4-三唑类化合物及其生理上可接受的盐在制备黄嘌呤氧化酶抑制剂中的应用。
  16. 权利要求1～11任一项所述的1,2,4-三唑类化合物及其生理上可接受的盐在制备预防或治疗黄嘌呤氧化酶相关疾病的药物中的应用。
  17. 根据权利要求16所述的应用，其特征在于，所述的黄嘌呤氧化酶相关疾病选自高尿酸血症、痛风。
PCT/CN2020/078082 2019-03-06 2020-03-05 1,2,4-三唑类化合物及其制法和药物用途 WO2020177752A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910167460.6A CN111662239B (zh) 2019-03-06 2019-03-06 1,2,4-三唑类化合物及其制法和药物用途
CN201910167460.6 2019-03-06

Publications (1)

Publication Number Publication Date
WO2020177752A1 true WO2020177752A1 (zh) 2020-09-10

Family

ID=72337674

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/078082 WO2020177752A1 (zh) 2019-03-06 2020-03-05 1,2,4-三唑类化合物及其制法和药物用途

Country Status (2)

Country Link
CN (1) CN111662239B (zh)
WO (1) WO2020177752A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892762A (en) * 1970-09-25 1975-07-01 Merck & Co Inc Novel substituted 1,2,4-triazoles
WO1997005878A1 (en) * 1995-08-10 1997-02-20 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
JP2008088107A (ja) * 2006-10-02 2008-04-17 Fujiyakuhin Co Ltd 新規ピリダジン誘導体
CN103210084A (zh) * 2010-06-16 2013-07-17 武田制药美国有限公司 黄嘌呤氧化还原酶抑制剂或黄嘌呤氧化酶抑制剂的新的改进的释放剂型

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848798B (zh) * 2012-11-30 2016-01-06 镇江新元素医药科技有限公司 2-芳基硒唑化合物及其药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892762A (en) * 1970-09-25 1975-07-01 Merck & Co Inc Novel substituted 1,2,4-triazoles
WO1997005878A1 (en) * 1995-08-10 1997-02-20 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
JP2008088107A (ja) * 2006-10-02 2008-04-17 Fujiyakuhin Co Ltd 新規ピリダジン誘導体
CN103210084A (zh) * 2010-06-16 2013-07-17 武田制药美国有限公司 黄嘌呤氧化还原酶抑制剂或黄嘌呤氧化酶抑制剂的新的改进的释放剂型

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BALDWIN, J. J. ET AL.: "4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1, 2, 4-triazoles, new classes of xanthine oxidase inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 18, no. 9, 1 September 1975 (1975-09-01), XP002670056, DOI: 20200604160348A *
SATO, T. ET AL.: "Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1, 2, 4-triazole derivatives as xanthine oxidoreductase inhibitors.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 1, 5 November 2008 (2008-11-05), XP025816902, DOI: 20200604152911 *
陆海波等 (LU, HAIBO ET AL.): "高尿酸血症治疗药物黄嘌呤氧化酶抑制剂的研究进展 (Research Process of Xanthine Oxidase Inhibitors as Hyperuricemia Drug)", 安徽医药 (ANHUI MEDICAL AND PHARMACEUTICAL JOURNAL), vol. 20, no. 4, 30 April 2016 (2016-04-30), XP55731696, DOI: 20200604105243A *

Also Published As

Publication number Publication date
CN111662239A (zh) 2020-09-15
CN111662239B (zh) 2023-07-28

Similar Documents

Publication Publication Date Title
CN113811300B (zh) Tead转录因子的新型小分子抑制剂
WO2021147879A1 (zh) Shp2抑制剂及其应用
RU2720488C2 (ru) Замещенные амино шестичленные насыщенные гетероалициклы в качестве ингибиторов dpp-iv длительного действия
JP5897566B2 (ja) 環式ｎ，ｎ’−ジアリールチオ尿素及びｎ，ｎ’−ジアリール尿素−アンドロゲン受容体アンタゴニスト、抗癌剤、その調製のための方法及び使用
CN105339350B (zh) 二氢吡啶酮mgat2抑制剂
EP2558087A1 (en) AMIDO COMPOUNDS AS RORyt MODULATORS AND USES THEREOF
TWI748996B (zh) 嘧啶類七元環化合物、其製備方法、藥用組合物及其應用
BR112017009012B1 (pt) Derivados de anel benzo de seis membros como inibidor de dpp-4 e uso dos mesmos
AU2022253683A1 (en) Deuterated dhodh inhibitors
CN108069954B (zh) 含no供体的喹唑啉酮化合物
RU2719484C2 (ru) Натриевая соль ингибитора транспортера мочевой кислоты и его кристаллическая форма
WO2016023330A1 (zh) 喹唑啉衍生物
CN103435562B (zh) 6-取代苯并二氮卓-2,4-二酮类化合物及其用途
CN116947756B (zh) 环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用
WO2020177752A1 (zh) 1,2,4-三唑类化合物及其制法和药物用途
CN109369554B (zh) 一种含有异羟肟酸的取代杂环类化合物及其制备方法和用途
TWI676625B (zh) 磺醯胺類衍生物、其製備方法及其在醫藥上的用途
CN106632245A (zh) 氮取代基苯基吡唑类黄嘌呤氧化还原酶抑制剂及制备与应用
CN107922375A (zh) 靶向idh2突变的抗肿瘤化合物及其使用方法
CN110903224A (zh) 一种芳基磺酰胺类化合物、其制备方法、药物组合物及用途
CN107459491A (zh) 含1,2,3‑三氮唑结构的苯甲酰胺类化合物及其用途
CN113354616B (zh) 二芳基-1,2,4-三唑类化合物及其制法和药物用途
JP4604147B2 (ja) クマリン誘導体
CN111072655A (zh) 一种三氮唑并吡啶类化合物及其制备方法和药用组合物与应用
CN112552303B (zh) 嘧啶酮并二氮杂卓类化合物及其盐、其制备方法及医药用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20766032

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20766032

Country of ref document: EP

Kind code of ref document: A1