CN113354616A - Diaryl-1, 2, 4-triazole compound, preparation method and pharmaceutical application thereof - Google Patents
Diaryl-1, 2, 4-triazole compound, preparation method and pharmaceutical application thereof Download PDFInfo
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- CN113354616A CN113354616A CN202010146796.7A CN202010146796A CN113354616A CN 113354616 A CN113354616 A CN 113354616A CN 202010146796 A CN202010146796 A CN 202010146796A CN 113354616 A CN113354616 A CN 113354616A
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- substituted
- halogen
- hydrogen
- alkoxy
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Images
Classifications
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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 formula I, a physiologically acceptable salt thereof, a preparation method, a pharmaceutical composition and application thereof, in particular to a compound shown in formula I and preparation thereofPreventing and treating gout or hyperuricemia related diseases.
Description
Technical Field
The invention relates to novel diaryl-1, 2, 4-triazoles of general formula (I) and to their physiologically acceptable salts. The use of these compounds in the prevention and treatment of hyperuricemia and gout, as well as methods for their use in therapy, and pharmaceutical compositions containing them.
Background
Statistics show that hyperuricemia and gout caused by the hyperuricemia become the second metabolic disease next to diabetes in the world. Hyperuricemia is a disease of uric acid metabolic disturbance, which causes the rise of uric acid level in blood, and is very easy to cause other metabolic diseases such as gout and the like. Gout is a joint disease caused by urate deposition, and is directly related to purine metabolic disorder and/or hyperuricemia caused by reduced uric acid excretion. Can be used for treating nephropathy complicated with metabolic diseases such as hyperlipidemia, hypertension, diabetes, arteriosclerosis and coronary heart disease. The prevalence rates of gout in different countries are different, the prevalence rate of gout in the United states reaches 3.76%, the prevalence rate of gout in the United kingdom is about 2.49%, the prevalence rate of gout in China is 1% -3%, and the prevalence rate of gout in China is about 1.2 hundred million patients with hyperuricemia. In recent years, 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 heavy burden is brought to the society and families.
The main routes for lowering uric acid levels in vivo include inhibiting uric acid production and promoting uric acid excretion. Xanthine oxidase inhibitors are important as key enzymes in the uric acid production metabolic pathway. According to 2016 Chinese gout diagnosis and treatment guide and gout diagnosis and treatment guide published by European Union and great Britain, the first-line uric acid reducing therapeutic drug is recommended to be xanthine oxidase inhibitor allopurinol; the second line uses the medicine that xanthine oxidase inhibitor febuxostat; sulfopyrrone, or probenecid, or benzbromarone, which are uricosuric drugs, may be used in patients resistant or intolerant to xanthine oxidase inhibitors; patients with substandard blood uric acid levels are treated with the optimal dosage of the single drug, and the single drug can be treated with a combination of a uricosuric drug and a xanthine oxidase inhibitor. The traditional 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 the development of a novel xanthine oxidase inhibitor with high efficiency and low toxicity 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 invention aims to provide a novel diaryl-1, 2, 4-triazole compound shown as 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 of the technical scheme of the invention, diaryl-1, 2, 4-triazole compounds shown in formula I and physiologically acceptable salts thereof are provided,
wherein X is selected from C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl and furyl, and the substituent is phenyl or pyridineMono-or polysubstitution on the radical, each independently selected from halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
Preferred are compounds of formula (IA) and physiologically acceptable salts thereof:
wherein X is selected from C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Is a mono-or polysubstituent group selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
Preferred are compounds of the general formula (IB) and physiologically acceptable salts thereof:
wherein X is selected from C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl; n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r3Is a mono-or polysubstituent group selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
Preferred are compounds of the general formula (IAa) and physiologically acceptable salts thereof:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
Preferred are compounds of formula (IAb) and physiologically acceptable salts thereof:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
Preferred are compounds of formula (IAc) and physiologically acceptable salts thereof:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
It is preferred to provide compounds of the general formula (IAd) and physiologically acceptable salts thereof:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group. .
Preferred are compounds of formula (IAe) and physiologically acceptable salts thereof:
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom; r1Is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl; r2Selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
In the general formula, the halogens are respectively and independently selected from F, Cl, Br and I; said C1-C6Each alkyl is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl; said C3-C6The cycloalkyl groups are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said C1-C3The alkoxy groups are each independently selected from methoxy, ethoxy, propoxy, isopropoxy.
Most preferred are the following compounds and their physiologically acceptable salts, wherein the compounds are selected from the group consisting of:
the diaryl-1, 2, 4-triazole compound provided by the invention has three isomers (I-1), (I-2) and (I-3), is collectively called diaryl-1, 2, 4-triazole, and is represented by a general formula (I).
Isomer (I-1)
Isomer (I-2)
Isomer (I-3)
In a second aspect of the present invention, there is provided a method for synthesizing a compound represented by formula I, comprising the steps of:
carrying out substitution reaction on the compound of the formula II to generate a compound of a formula III, carrying out hydrazinolysis on the compound of the formula III to obtain a compound of a formula IV, and reacting the compound of the formula IV with a cyano compound to generate a compound of a formula I:
wherein n, X, Y, R1And Ar is as defined for the first aspect, R4Is methyl or ethyl.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of 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 formula I are mixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavors and colors in a known manner and are tableted or coated, or are 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 the compound shown in the general formula I and a pharmaceutically acceptable carrier.
Pharmacological research shows that the compound of the general formula I has the activity of inhibiting xanthine oxidase and can effectively reduce the level of in vivo uric acid, thereby achieving the purpose of treatment.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, capsule, and coating agent, and the parenteral preparation can be 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, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
In a fourth aspect of the present invention, there is provided a use of the compound of the first aspect and physiologically acceptable salts thereof for the preparation of xanthine oxidase inhibitors.
The fourth aspect also provides the use of the compound of the first aspect and physiologically acceptable salts thereof in the manufacture of a medicament for the prevention or treatment of xanthine oxidase related diseases. The disease is selected from hyperuricemia and gout.
Drawings
FIG. 1 Effect of Compound TAZ-3-19 on the level of uric acid in the blood of mice model of acute hyperuricemia
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). The NMR shifts (δ) are given in parts per million (ppm). m.p. is the melting point given in ° c, the temperature is uncorrected. The column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was measured using INOVA-300 and CDCl as the solvent3、DMSO-D6The internal standard is TMS and the chemical shifts are given in ppm. MS was measured using an Agilent LC/MSD TOF LC/MS spectrometer.
Example 1: TAZ-3-16
a) In a 100mL round-bottom flask were added ethyl 4-hydroxy-3, 5-dichlorobenzoate (2.35g,10mmol), N- (3-chloropropyl) piperidine (1.93g,12mmol), potassium carbonate (2.76g,20mmol), DMF (15mL), respectively, reacted at 80 ℃ for 12 hours, 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, and dried over anhydrous sodium sulfate for further use.
b) A100 mL round-bottom flask was charged with the product, hydrazine hydrate (80% N)2H45mL) and ethanol (20mL) are reacted at 90 ℃ for 6 hours under reflux, the color of the solution is changed from dark to light, TLC detection is carried out after the reaction, the raw materials are completely reacted, ethanol and excess hydrazine hydrate are evaporated, yellow solid is generated, the yellow solid is washed by a mixed solvent (petroleum ether: ethyl acetate ═ 1:1), and the mixture is dried for standby.
c) 4-cyanopyridine (156mg,1mmol), substituted benzoyl hydrazine (345mg,1mmol), potassium carbonate (276mg,2mmol), n-butanol (3mL) were sequentially added to a microwave reaction sealed tube, and reacted at 125 ℃ for 12 hours, after which the solvent was distilled off, 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 obtain 254mg of a yellow solid, with a yield of 58.8%.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that N- (3-chloropropyl) piperidine from example 1 is replaced by N- (3-chloropropyl) pyrrole.1H NMR(400MHz,DMSO-d6)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 process is similar to example 1, except that 3-chloro-1-diethylaminopropane is used instead of N- (3-chloropropyl) piperidine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 1- (3-chloropropyl) -4-methylpiperazine is used instead of N- (3-chloropropyl) piperidine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 2-fluorobenzonitrile is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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
The preparation is analogous to example 1, except that 3-fluorobenzonitrile is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 procedure is analogous to example 1, except that 4-trifluoromethylbenzonitrile is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 procedure is analogous to example 1, except that 4-iodobenzonitrile is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 is carried out analogously to example 1 by replacing 4-cyanopyridine in example 1 with 3-cyanopyridine.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 2-cyanopyridine is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 2-cyanofuran is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 2-methyl-4-cyanopyridine is used instead of 3-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that 2-fluoro-4-cyanopyridine is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 procedure is analogous to example 1, except that 2-chloro-4-cyanopyridine is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 procedure is analogous to example 1, except that 2-bromo-4-cyanopyridine is used instead of 4-cyanopyridine in example 1.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate from example 1 is replaced by methyl 3-fluoro-4-hydroxybenzoate.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate from example 1 is replaced by methyl 3-chloro-4-hydroxybenzoate.1H NMR(400MHz,DMSO-d6)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
The preparation is analogous to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate from example 1 is replaced by methyl 3-bromo-4-hydroxybenzoate.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate from example 1 is replaced by methyl 3-iodo-4-hydroxybenzoate.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate from example 1 is replaced by methyl 3-trifluoromethyl-4-hydroxybenzoate.1H NMR(400MHz,DMSO-d6)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 process is similar to example 1, except that ethyl 4-hydroxy-3, 5-dichlorobenzoate in example 1 is replaced with methyl 4-mercaptobenzoate.1H NMR(400MHz,DMSO-d6)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 is analogous to example 1, except that N- (2-chloropropyl) pyrrole is used instead of N- (3-chloropropyl) piperidine in example 1.1H NMR(400MHz,DMSO-d6)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 is similar to example 1, except that N- (2-chloropropyl) butylamine is used instead of N- (3-chloropropyl) piperidine in example 1.1H NMR(400MHz,DMSO-d6)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 method for inhibiting the xanthine oxidase by using the compound of the invention comprises the following steps:
taking febuxostat and topiroxostat as positive controls, and determining the content of each compound at 10 mu mol.L by a colorimetric method-1The single-concentration inhibition rate of xanthine oxidase at the concentration was determined, and the half-effective Inhibitory Concentration (IC) of the compound having a high single-concentration inhibition rate against xanthine oxidase was determined50)。
The specific method comprises the following steps: test samples were dissolved in DMSO and formulated into 10mM stock solutions. The effect of each compound on XOD-catalyzed Xanthine (XAN) hydrolysis was determined at 37 ℃ and pH7.4 using 96-well plates. The reaction system contained 10. mu. mol. L-13U/L XOD (control group not added, replaced with 0.01% DMSO), and buffer (3.5mM KH)2PO4,15.2mM K2HPO40.25mM EDTA, and 50. mu.M XAN, pH 7.4). Measuring absorption of uric acid at 293nm wavelength with spectrophotometer to determine XOD-catalyzed Xanthine (XAN) hydrolysis, calculating inhibition rate according to OD value, and calculating IC according to single concentration inhibition rate selectivity50The value is obtained.
As a result:
the final concentration of each of the above-mentioned compounds was determined to be 10-5μmol·L-1The inhibition rate of xanthine oxidase; determination and calculation of IC's for several Compounds of the invention50The value is obtained. The results are shown in Table 1.
TABLE 1 xanthine oxidase inhibition by compounds
Experimental example 2: effect of compound TAZ-3-16 of the present invention on reducing blood uric acid level in hyperuricemia mice
The method comprises the following steps:
an ICR mouse with the weight of 24-26 g is continuously stimulated for multiple times by hypoxanthine and oteracil potassium, and an animal with stably increased blood uric acid level is selected as a (HUA) model mouse. The model mice were randomly divided into 3 groups (n ═ 10): model control, febuxostat and compound TAZ-3-16 groups, water, positive control drug febuxostat 1mg/kg, and compound TAZ-3-160.5 mg/kg were administered by intragastric gavage, respectively. The administration is performed 1 time per day for 2 days, and blood is taken from the tail tip to determine the level of hematuric acid. The same batch of normal ICR mice was gavaged with water as a normal control group.
As a result:
the blood uric acid levels of the animals of each group are shown in table 2: the blood uric acid level of the model control group animals was significantly increased compared to the normal control group. Compared with a model control group, the mean of the hematuria water of the febuxostat group and the TAZ-3-16 group is obviously reduced.
TABLE 2 blood uric acid lowering Effect of compound TZA-3-16 on HUA model mice.
P <0.001vs normal control group; # and p <0.001vs model control group
Experimental example 3: the compound TAZ-3-19 of the invention has the effect of reducing the blood uric acid level of mice with acute hyperuricemia
The method comprises the following steps:
ICR mice, weighing 24-26 g, purchased from Wittingle. A method of combining hypoxanthine and oteracil potassium for stimulation is adopted to form a mouse model of acute hyperuricemia. The model mice were randomly divided into 5 groups (n ═ 10): the model, febuxostat and the compounds TAZ-3-19-0.625, TAZ-3-19-1.25 and TAZ-3-19-2.5 are respectively administered with water by intragastric gavage, the positive control drug febuxostat 5mg/kg, and the compounds TAZ-3-190.625 mg/kg, 1.25mg/kg and 2.5 mg/kg. The same batch of normal ICR mice were gavaged with water as a normal control group, and the level of hematuric acid was measured by tail tip curve before and 1h, 2h and 4h after administration.
As a result:
the blood uric acid level of the model control group animals was significantly increased compared to the normal control group. Compared with the model control group, the peak values of blood uric acid 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 (FIG. 1, Table 3).
TABLE 3 Effect of Compound TZA-3-19 on lowering blood uric acid levels in mice model for acute hyperuricemia
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 C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl and furyl, the substituent is one or more substituent groups on the phenyl or pyridyl, and each substituent group is independently selected from halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
2. A compound according to claim 1 and the physiologically acceptable salts thereof, characterized in that the compound is of the general formula (IA):
wherein X is selected from C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2is a mono-or polysubstituent group selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
3. The compound of claim 1, wherein the compound is a compound of formula (IB) and physiologically acceptable salts thereof:
wherein X is selected from C1-C6Alkyl-substituted amino, C3-C6Cycloalkyl-substituted amino, pyrrolyl, piperidinyl and piperazinyl;
n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R3is a mono-substituted or multi-substituted group selected from hydrogen, halogen,C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl.
4. A compound according to claim 2, and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAa):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
5. A compound according to claim 2 and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAb):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
6. A compound according to claim 2 and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAc):
wherein n is 1,2,3,4 or 5; y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
7. A compound according to claim 2 and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAd):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
8. A compound according to claim 2 and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAe):
wherein n is 1,2,3,4 or 5;
y is selected from oxygen or sulfur atom;
R1is a mono-substituted or multi-substituted group on a benzene ring, and is selected from hydrogen, halogen and C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, trifluoromethyl;
R2selected from hydrogen, halogen, C1-C3Alkyl radical, C1-C3An alkoxy group.
9. The compound according to claim 1, 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 a formula III, carrying out hydrazinolysis on the compound of the formula III to obtain a compound of a formula IV, and reacting the compound of the formula IV with a cyano compound to generate a compound of a formula I:
wherein n, X, Y, R1And Ar is as defined in any one of claims 1 to 9, R4Is methyl or ethyl.
11. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9, 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 microparticle delivery systems.
13. Use of a compound according to any one of claims 1 to 9, and physiologically acceptable salts thereof, for the manufacture of xanthine oxidase inhibitors.
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 a xanthine oxidase related disease.
15. The use according to claim 14, wherein said disease is selected from the group consisting of hyperuricemia and gout.
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| 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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| 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 |
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