CN113354616B - Diaryl-1, 2, 4-triazole compound and preparation method and pharmaceutical application thereof - Google Patents

Diaryl-1, 2, 4-triazole compound and preparation method and pharmaceutical application thereof Download PDF

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CN113354616B
CN113354616B CN202010146796.7A CN202010146796A CN113354616B CN 113354616 B CN113354616 B CN 113354616B CN 202010146796 A CN202010146796 A CN 202010146796A CN 113354616 B CN113354616 B CN 113354616B
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alkyl
halogen
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cycloalkyl
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CN113354616A (en
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肖志艳
叶菲
杨亚军
田金英
严定安
张晓琳
候现新
姜楠
杨颖�
李雪晨
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Institute of Materia Medica of CAMS
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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

Abstract

The invention belongs to the technical field of medicines, and discloses a 1,2, 4-triazole compound shown in a formula I, physiologically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof, in particular to a compound shown in the formula I and application thereof in preparing medicines for preventing and treating gout or diseases related to hyperuricemia.

Description

Diaryl-1, 2, 4-triazole compound and preparation method and pharmaceutical application thereof
Technical Field
The present invention relates to novel diaryl-1, 2, 4-triazoles of the general formula I, and to their physiologically acceptable salts. The use of these compounds in the prophylaxis and treatment of hyperuricemia and gout, methods for their use in therapy, and pharmaceutical compositions containing them.
Background
It has been shown statistically that hyperuricemia and its induced gout have become the second most metabolic disease worldwide, next to diabetes. Hyperuricemia is a disease which is caused by uric acid metabolic disorder and causes the rise of uric acid level in blood, and other metabolic diseases such as gout are extremely easy to cause. Gout is an arthropathy caused by urate deposition and is directly related to hyperuricemia caused by purine metabolic disorder and/or reduced uric acid excretion. Can be used for treating renal diseases, such as hyperlipidemia, hypertension, diabetes, arteriosclerosis, and coronary heart disease. The prevalence of gout in different countries is different, the prevalence of gout in the United states reaches 3.76%, the prevalence of gout in the United kingdom is about 2.49%, and the prevalence of gout in China is 1% -3% and is about 1.2 hundred million hyperuricemia patients at present. In recent years, along with the improvement of the living standard of people in China, the incidence rate of hyperuricemia and gout also tends to rise year by year, and a heavy burden is brought to society and families.
The main pathways for lowering uric acid levels in the body include inhibiting uric acid production and promoting uric acid excretion. And xanthine oxidase inhibitors are important as key enzymes in the uric acid production metabolic pathway. According to the diagnosis and treatment guidelines for gout issued by the European Union and the United kingdom, the first-line uric acid reducing therapeutic drug is recommended to be xanthine oxidase inhibitor allopurinol; the second line medicine is xanthine oxidase inhibitor febuxostat; patients with resistance or intolerance to xanthine oxidase inhibitors may use uric acid excretion promoting drugs such as bupirimate, probenecid, or benzbromarone; the optimal dosage of single medicine for treating patients with blood uric acid level not reaching the standard can be combined with uric acid excretion promoting medicine and xanthine oxidase inhibitor. The conventional xanthine oxidase inhibitors on the market at present have limited types and have the problems of tolerance, toxic and side effects and the like, so that development of new high-efficiency low-toxicity xanthine oxidase inhibitors is urgently needed.
The invention aims to provide a novel diaryl-1, 2, 4-triazole compound which has xanthine oxidase inhibitory activity and can be used for treating hyperuricemia and gout.
Disclosure of Invention
The technical problem solved by the invention is to provide a novel diaryl-1, 2, 4-triazole compound shown in a formula I, and a preparation method, a pharmaceutical composition and application thereof.
In order to achieve the purpose of the invention, the invention provides the following technical scheme:
in a first aspect, the invention provides diaryl-1, 2, 4-triazole compounds shown in formula I and physiologically acceptable salts thereof,
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, furyl, said substituents being phenyl or mono-or polysubstituted on pyridyl, each independently selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl.
Preferred are compounds of formula (IA) and their physiologically acceptable salts:
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Is monosubstituted or polysubstitutedA substituent group selected from hydrogen, halogen, C 1- C 6 Alkyl, C 3- C 6 Cycloalkyl, C 1- C 3 Alkoxy, trifluoromethyl.
Preferred are compounds of formula (IB) and physiologically acceptable salts thereof:
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 3 Is a monosubstituted or polysubstituted group selected from hydrogen, halogen, C 1- C 6 Alkyl, C 3- C 6 Cycloalkyl, C 1- C 3 Alkoxy, trifluoromethyl.
Preferred are compounds of the general formula (IAa) and their physiologically acceptable salts:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
Preferred are compounds of the general formula (IAb) and their physiologically acceptable salts:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
Preferred are compounds of the general formula (IAc) and their physiologically acceptable salts:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
It is preferable to provide a compound represented by the general formula (IAd):
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
Preferred are compounds of the general formula (IAe) and their physiologically acceptable salts:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms; r is R 1 Is a mono-or polysubstituted 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; r is R 2 Selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
In the general formula, the halogen is independently selected from F, cl, br, I; the C is 1- C 6 Alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl; the C is 3- C 6 Cycloalkyl groups are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the C is 1- C 3 The alkoxy groups are each independently selected from methoxy, ethoxy, propoxy, isopropoxy.
Most preferred are the compounds described below, and their physiologically acceptable salts, characterized in that said compounds are selected from the group consisting of:
the present invention provides the diaryl-1, 2, 4-triazole compound, wherein three isomers (I-1), (I-2) and (I-3) exist, and the diaryl-1, 2, 4-triazole compound is generally called as diaryl-1, 2, 4-triazole and is represented by a general formula (I).
Isomer (I-1)
Isomer (I-2)
Isomer (I-3)
The second aspect of the technical scheme of the invention provides a synthesis method of a compound shown in a formula I, which comprises the following steps:
carrying out substitution reaction on the compound of the formula II to generate a compound of the formula III, carrying out hydrazinolysis on the compound of the formula III to obtain a compound of the formula IV, and reacting the compound of the formula IV with a cyano compound to generate a compound of the formula I:
therein, n, X, Y, R 1 And Ar is as defined in the first aspect, R 4 Is methyl or ethyl.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect and a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
For the preparation of medicaments, the compounds of the general formula I can be admixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavourings and pigments in a known manner and formulated as tablets or coated tablets or suspended or dissolved in water or oil with other additional substances.
The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of a compound as shown in the general formula I and a pharmaceutically acceptable carrier.
Pharmacological studies show that the compound of the general formula I has the activity of inhibiting xanthine oxidase, and can effectively reduce the blood uric acid level in vivo, thereby achieving the purpose of treatment.
The compounds of the present invention may be administered orally or parenterally. The oral administration can be tablet, capsule, and coating agent, and parenteral administration dosage forms include injection and suppository. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, and coatings are conventional adjuvants such as starch, gelatin, acacia, silica, polyethylene glycol, and solvents for liquid dosage forms such as water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. Other adjuvants may also be present in the formulations containing the compounds of the invention, such as surfactants, lubricants, disintegrants, preservatives, flavouring agents, pigments and the like.
According to a fourth aspect of the present invention there is provided the use of a compound according to the first aspect and physiologically acceptable salts thereof for the preparation of xanthine oxidase inhibitors.
In a fourth aspect, there is also provided the use of a compound according to the first aspect, and physiologically acceptable salts thereof, in the manufacture of a medicament for the prophylaxis or treatment of xanthine oxidase-related diseases. The diseases are selected from hyperuricemia and gout.
Drawings
FIG. 1 influence of the Compound TAZ-3-19 on blood uric acid levels in mice with acute hyperuricemia models
Detailed Description
The invention is further illustrated below with reference to examples, which are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). NMR displacements (δ) are given in parts per million (ppm). The m.p. is the melting point given in degrees Celsius, the temperature being uncorrected. Column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was performed using INOVA-300 with CDCl as the solvent 3 、DMSO-D 6 Internal standard is TMS and chemical shifts are given in ppm. The MS was determined using an Agilent LC/MSD TOF LC/MS.
Example 1: TAZ-3-16
a) To a 100mL round bottom flask was added ethyl 4-hydroxy-3, 5-dichlorobenzoate (2.35 g,10 mmol), N- (3-chloropropyl) piperidine (1.93 g,12 mmol), potassium carbonate (2.76 g,20 mmol), DMF (15 mL), and after completion of the reaction, most of the DMF was distilled off, the residue was dissolved in water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and kept ready for use.
b) A100 mL round bottom flask was charged with the above product, hydrazine hydrate (80% N 2 H 4 5 mL), ethanol (20 mL), reflux-reacting for 6h at 90 ℃, detecting the color of the solution from dark to light, detecting the reaction of the raw materials by TLC after the reaction, evaporating ethanol and excessive hydrazine hydrate to obtain yellow solid, washing with mixed solvent (petroleum ether: ethyl acetate=1:1), and drying for later use.
c) 4-cyanopyridine (156 mg,1 mmol), substituted benzoyl hydrazine (345 mg,1 mmol), potassium carbonate (276 mg,2 mmol), n-butanol (3 mL) were added in sequence to a microwave reaction tube, the reaction was carried out at 125℃for 12h, the solvent was distilled off after the reaction, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (dichloromethane: methanol=50:1) to give 254mg of yellow solid in 58.8% yield. 1 H 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).
Example 2: TAZ-3-17
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) piperidine in example 1 was replaced by N- (3-chloropropyl) pyrrole. 1 H 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).
Example 3: TAZ-3-18
The preparation was carried out in analogy to example 1, except that 3-chloro-1-diethylaminopropane was used instead of N- (3-chloropropyl) piperidine in example 1. 1 H 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).
Example 4: TAZ-3-19
The preparation was carried out in analogy to example 1, except that 1- (3-chloropropyl) -4-methylpiperazine was used instead of N- (3-chloropropyl) piperidine in example 1. 1 H 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).
Example 5: TAZ-3-48
The preparation was carried out in analogy to example 1, except that 2-fluorobenzonitrile was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 6: TAZ-3-49
Preparation method and implementationExample 1 is similar except that 3-fluorobenzonitrile is used in place of the 4-cyanopyridine in example 1. 1 H 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).
Example 7: TAZ-3-51
The preparation was carried out in analogy to example 1, except that 4-cyanopyridine in example 1 was replaced by 4-trifluoromethylbenzonitrile. 1 H 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).
Example 8: TAZ-3-58
The preparation was carried out in analogy to example 1, except that 4-cyanopyridine was replaced with 4-iodobenzonitrile in example 1. 1 H 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).
Example 9: TAZ-3-60
The preparation was carried out in analogy to example 1, substituting 3-cyanopyridine for 4-cyanopyridine in example 1. 1 H 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).
Example 10: TAZ-3-61
The preparation was similar to example 1, except that 2-cyanopyridine was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 11: TAZ-3-62
The preparation was similar to example 1, except that 2-cyanofuran was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 12: TAZ-3-63
The preparation was similar to example 1, except that 2-methyl-4-cyanopyridine was used instead of 3-cyanopyridine in example 1. 1 H 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).
Example 13: TAZ-3-64
The preparation was carried out in analogy to example 1, except that 2-fluoro-4-cyanopyridine was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 14: TAZ-3-65
The preparation was carried out in analogy to example 1, except that 2-chloro-4-cyanopyridine was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 15: TAZ-3-66
The preparation was carried out in analogy to example 1, except that 2-bromo-4-cyanopyridine was used instead of 4-cyanopyridine in example 1. 1 H 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).
Example 16: TAZ-3-69
The preparation was carried out in analogy to example 1, except that methyl 3-fluoro-4-hydroxybenzoate was used instead of ethyl 4-hydroxy-3, 5-dichlorobenzoate as in example 1. 1 H 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).
Example 17: TAZ-3-70
The preparation was carried out in analogy to example 1, except that methyl 3-chloro-4-hydroxybenzoate was used instead of ethyl 4-hydroxy-3, 5-dichlorobenzoate as in example 1. 1 H 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).
Example 18: TAZ-3-71
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The preparation was carried out in analogy to example 1, except that methyl 3-bromo-4-hydroxybenzoate was used instead of ethyl 4-hydroxy-3, 5-dichlorobenzoate as in example 1. 1 H 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).
Example 19: TAZ-3-72
The preparation was carried out in analogy to example 1, except that methyl 3-iodo-4-hydroxybenzoate was used instead of ethyl 4-hydroxy-3, 5-dichlorobenzoate in example 1. 1 H 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).
Example 20: TAZ-3-74
The preparation was carried out in analogy to example 1, except that methyl 3-trifluoromethyl-4-hydroxybenzoate was used instead of ethyl 4-hydroxy-3, 5-dichlorobenzoate as in example 1. 1 H 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).
Example 21: TAZ-3-75
The preparation was carried out in analogy to example 1, except that 4-hydroxy-3, 5-dichlorobenzoic acid ethyl ester in example 1 was replaced with methyl 4-mercaptobenzoate. 1 H 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).
Example 22: TAZ-3-79
The preparation was carried out in analogy to example 1, except that N- (2-chloropropyl) pyrrole was used instead of N- (3-chloropropyl) piperidine in example 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.80–8.73(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).
Example 23: TAZ-3-80
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) piperidine in example 1 was replaced by N- (2-chloropropyl) butylamine. 1 H 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).
Pharmacological experiments
Experimental example 1: the inhibition method of xanthine oxidase by the compound of the invention comprises the following steps:
using febuxostat and topiroxostat as positive control, and determining each compound at 10mu mol.L by colorimetric method -1 Single-concentration inhibition ratio of xanthine oxidase at concentration, and half-effective Inhibition Concentration (IC) of xanthine oxidase was further measured for a compound having a higher single-concentration inhibition ratio 50 )。
The specific method comprises the following steps: test samples were dissolved in DMSO to prepare 10mM stock solutions. The effect of each compound on the hydrolysis of Xad-catalyzed Xanthine (XAN) was measured at 37℃and pH7.4 using 96-well plates. The reaction system contains 10 mu mol.L -1 3U/L XOD (control was not added, 0.01% DMSO instead), and buffer (3.5 mM KH 2 PO 4 ,15.2mM K 2 HPO 4 0.25mM EDTA, and 50. Mu.M XAN, pH 7.4). Detecting absorption of uric acid by spectrophotometry at 293nm wavelength to determine XOD-catalyzed Xanthine (XAN) hydrolysis, calculating inhibition ratio according to OD value, and selectively calculating IC according to single concentration inhibition ratio 50 Values.
Results:
the final concentration of the above compounds was determined to be 10 -5 μmol·L -1 The inhibition rate of xanthine oxidase; determination and calculation of IC for several compounds of the invention 50 Values. The results are shown in Table 1.
TABLE 1 inhibition of xanthine oxidase by Compounds
Experimental example 2: action of the Compound TAZ-3-16 of the invention on reducing blood uric acid level in hyperuricemia mice
The method comprises the following steps:
ICR mice weighing 24-26 g, and selecting animals with stable and elevated blood uric acid water as (HUA) model mice by adopting a method of continuously stimulating with hypoxanthine and potassium oxazinate for multiple times. Model mice were randomly divided into 3 groups (n=10): model control, febuxostat, and compound TAZ-3-16 groups were given by gavage with water, positive control febuxostat 1mg/kg, and compound TAZ-3-16.5 mg/kg, respectively. The administration was carried out 1 time a day for 2 days continuously, and blood was taken from the tail tip to measure the blood uric acid level. The same batch of normal ICR mice were given water as a normal control group by gavage.
Results:
blood uric acid levels for each group of animals are shown in table 2: the blood uric acid level of the animals of the model control group was significantly increased compared to the normal control group. The mean blood uric acid level was significantly reduced in the febuxostat group and in the TAZ-3-16 group compared to the model control group.
TABLE 2 blood uric acid lowering effect of Compounds TZA-3-16 on HUA model mice.
* P <0.001vs normal control group; # #, p <0.001vs model control group
Experimental example 3: effect of the inventive compound TAZ-3-19 on lowering blood uric acid level in acute hyperuricemia mice
The method comprises the following steps:
ICR mice, weighing 24-26 g, purchased from Vetong Lihua. The method of combining hypoxanthine and potassium oxazinate stimulation is adopted to form an acute hyperuricemia mouse model. Model mice were randomly divided into 5 groups (n=10): model, febuxostat, and compound TAZ-3-19-0.625, TAZ-3-19-1.25, TAZ-3-19-2.5, respectively, were administered by gavage with water, positive control febuxostat 5mg/kg, and compound TAZ-3-19.625 mg/kg, 1.25mg/kg, 2.5mg/kg. The same batch of normal ICR mice were given water by lavage as a normal control group, and blood uric acid levels were measured via the tail tip curves before, 1h, 2h, and 4h after administration, respectively.
Results:
the blood uric acid level of the animals of the model control group was significantly increased compared to the normal control group. The peak blood uric acid values of the TAZ-3-19-0.625, TAZ-3-19-1.25 and TAZ-3-19-2.5 groups were reduced by 5.7%, 34.2% and 68.0%, respectively, as compared to the model control group (FIG. 1, table 3).
TABLE 3 action of Compounds TZA-3-19 for reducing blood uric acid levels in mice with acute hyperuricemia models
* P <0.001vs normal control group; # #, p <0.001vs model control group.

Claims (15)

1. A diaryl-1, 2, 4-triazole compound represented by the following general formula (I) and a physiologically acceptable salt thereof,
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolidinyl, piperidinyl, and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, furyl, wherein the substituent is a single or multiple substituent on the phenyl or pyridyl, which is a compound of formula (I)Each independently selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl.
2. The compound of claim 1, wherein said compound is of formula (IA):
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolidinyl, piperidinyl, and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 is a monosubstituted or polysubstituted group selected from halogen, C 1- C 6 Alkyl, C 3- C 6 Cycloalkyl, C 1- C 3 Alkoxy, trifluoromethyl.
3. The compound of claim 1 and physiologically acceptable salts thereof, wherein the compound is of formula (IB):
wherein X is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, pyrrolidinyl, piperidinyl, and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1- C 6 Alkyl, C 3- C 6 Cycloalkyl, C 1- C 3 Alkoxy, trifluoromethyl;
R 3 is a monosubstituted or polysubstituted group selected from halogen, C 1- C 6 Alkyl, C 3- C 6 Cycloalkyl, C 1- C 3 Alkoxy, trifluoromethyl.
4. The compound of claim 2, wherein said compound is of formula (IAa):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 selected from halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
5. The compound of claim 2, wherein the compound is of formula (IAb):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 selected from halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
6. The compound of claim 2, wherein the compound is of formula (IAc):
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 selected from halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
7. The compound of claim 2, wherein the compound is of formula (IAd):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 selected from halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
8. The compound of claim 2, wherein the compound is of formula (IAe):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atoms;
R 1 is a mono-or polysubstituted group on the benzene ring selected from halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy, trifluoromethyl;
R 2 selected from halogen, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group.
9. The compound of claim 1, and physiologically acceptable salts thereof, wherein said compound is selected from the group consisting of:
10. a process for the preparation of a compound according to any one of claims 1 to 9, comprising the steps of:
carrying out substitution reaction on the compound of the formula II to generate a compound of the formula III, carrying out hydrazinolysis on the compound of the formula III to obtain a compound of the formula IV, and reacting the compound of the formula IV with a cyano compound to generate a compound of the formula I:
therein, n, X, Y, R 1 Ar is as defined in any one of claims 1 to 9, R 4 Is methyl or ethyl.
11. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations, and various particulate delivery systems.
13. Use of a compound according to any one of claims 1 to 9, or a physiologically acceptable salt thereof, for the preparation of a xanthine oxidase inhibitor.
14. Use of a compound according to any one of claims 1 to 9, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of xanthine oxidase-related diseases.
15. Use according to claim 14, characterized in that said disease is selected from hyperuricemia, gout.
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Citations (6)

* 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
CN1561340A (en) * 2002-01-28 2005-01-05 株式会社富士药品 Novel 1,2,4-triazole compound
JP2008088107A (en) * 2006-10-02 2008-04-17 Fujiyakuhin Co Ltd New pyridazine derivative
CN103210084A (en) * 2010-06-16 2013-07-17 武田制药美国有限公司 Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
CN103848798A (en) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司 2-Arylselenazole compounds and medicinal composition thereof

Patent Citations (6)

* 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
CN1561340A (en) * 2002-01-28 2005-01-05 株式会社富士药品 Novel 1,2,4-triazole compound
JP2008088107A (en) * 2006-10-02 2008-04-17 Fujiyakuhin Co Ltd New pyridazine derivative
CN103210084A (en) * 2010-06-16 2013-07-17 武田制药美国有限公司 Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
CN103848798A (en) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司 2-Arylselenazole compounds and medicinal composition thereof

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