WO2020177752A1 - Composé de 1,2,4-triazole, procédé de préparation correspondant et utilisation pharmaceutique associée - Google Patents

Composé de 1,2,4-triazole, procédé de préparation correspondant et utilisation pharmaceutique associée Download PDF

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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
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substitution
mono
ortho
compound
cycloalkyl
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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
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中国医学科学院药物研究所
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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
    • 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.

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Abstract

La présente invention se rapporte au domaine technique de la médecine, et concerne en particulier un composé de 1,2,4-triazole représenté par la formule (I) et un sel physiologiquement acceptable de celui-ci, un procédé de préparation du composé, une préparation pharmaceutique contenant le composé, et une utilisation du composé dans la préparation de médicaments pour la prévention et le traitement de maladies associées à l'hyperuricémie.
PCT/CN2020/078082 2019-03-06 2020-03-05 Composé de 1,2,4-triazole, procédé de préparation correspondant et utilisation pharmaceutique associée WO2020177752A1 (fr)

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Citations (4)

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WO1997005878A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation
JP2008088107A (ja) * 2006-10-02 2008-04-17 Fujiyakuhin Co Ltd 新規ピリダジン誘導体
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WO1997005878A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation
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

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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 *

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