CN106146419A - Xanthine oxidase inhibitor - Google Patents
Xanthine oxidase inhibitor Download PDFInfo
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- CN106146419A CN106146419A CN201610630599.6A CN201610630599A CN106146419A CN 106146419 A CN106146419 A CN 106146419A CN 201610630599 A CN201610630599 A CN 201610630599A CN 106146419 A CN106146419 A CN 106146419A
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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
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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Abstract
The invention belongs to pharmaceutical technology field, relate to 2 (3 cyano group/nitro 4 substituted-phenyl) 4 methyl 2 with the formula I of xanthine oxidase inhibitory activityH1,2,3 triazole 4 formic acid and formylhydrazine compounds, pharmaceutically useful salt, pharmaceutically useful solvate and preparation method thereof, wherein, each substituent group of compound defines as described in claims and description.The invention still further relates to these compounds purposes in preparation treatment hyperuricemia and goat medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to a series of xanthine oxidase inhibitor, be specifically related to 2-(3-cyanogen
Base/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid or 2-(3-cyano group/nitro-4-substituted benzene
Base)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compounds and application thereof.
Background technology
Gout is a kind of global metabolic disease, and the height of its prevalence is practised by economic development level, environment, diet
The impact of the many factors such as used, race, heredity, medical level, diagnostic criteria and statistical method, various countries report and differ greatly.Closely
Nian Lai, no matter in American-European countries or in countries in Asia, the prevalence of gout has the trend increased year by year.China's antihyperuricemic
The prevalence of disease and gout the most linearly ascendant trend, has statistics to show, the prevalence total in all age bracket gouts is about
0.84%.
Gout is that too much and kidney Scavenging activity declines due to internal generation uric acid, and uric acid is accumulated in vivo, causes uric acid
Salt-pepper noise precipitates in joint and each internal organs.Clinical treatment gout medicine is broadly divided into promotion urate excretion and suppression uric acid is raw at present
Become, and use adequate measure to improve related symptoms.Along with the raising of living standards of the people, the most various animal foods are at drink
Food structure in proportion be gradually increased so that the most rare prevalence of gout with increase day by day.How to develop a kind of effective, safety
And the medicine of taking convenience has become the problem continuing to solve.In decades, allopurinol is the most unique one
For suppressing the medicine of uricopoiesis, and the gold medicine as gout is widely used in clinic, but needs to repeat heavy dose
It is administered the levels of drugs remaining higher, causes the most fatal serious untoward reaction caused by drug accumulation simultaneously.How to open
Send out a kind of effectively, safety and the medicine of taking convenience has become the problem continuing to solve.The disappearance of medicine, to novel
The exploitation of medicine brings huge commercial opportunities.
Febuxostat (febuxostat) is first disclosed as in WO9209279A1, for a new generation's xanthine oxidase suppression
Agent, is used for treating the too high disease of uric acid (gout) clinically, and this medicine is that Teijin Ltd of Japan (Teijin) was in year in 2004
Just listing in Japanese publication, its end of the year lists at U. S. application, and IPSEN company is in Europe application listing；European Union is in May, 2008
Its listing of part approval.
2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid and formyl hydrazine
Compound has not yet to see report as the research of xanthine oxidase inhibitor.
Summary of the invention
It is an object of the invention to design, synthesize the 2-(3-cyano group/nitre with good xanthine oxidase inhibitory activity
Base-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid or 2-(3-cyano group/nitro-4-substituted-phenyl)-4-first
Base-2H-1,2,3-triazole-4-formylhydrazine compounds；Prepared compound shows good xanthine oxidase to be pressed down
Make use, can be used for preparation treatment hyperuricemia and goat medicine.
The general structure of the object of the present invention is as follows:
Wherein: X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C10Alkyl,
C3-C10Allylic alkylation, C3-C10Alkynes alkyl, C4-C7Cycloalkyl-alkyl, C7-C10Aryl alkyl.
Preferably, X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C8Alkyl,
C3-C8Allylic alkylation, C3-C8Alkynes alkyl, C4-C6Cycloalkyl-alkyl, C7-C9Aryl alkyl.
It is highly preferred that X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C6Alkane
Base, C3-C6Allylic alkylation, C3-C6Alkynes alkyl, C4-C6Cycloalkyl-alkyl, C7-C9Aryl alkyl.
It is further preferred that X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is ethyl, n-pro-pyl, isopropyl, just
Butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, tertiary amyl, benzyl, pi-allyl.
It is the most acceptable nontoxic that the compound of the present invention also includes that derivant shown in structure above is formed
Salt and hydrate thereof or other prodrug forms, these pharmaceutically acceptable nontoxic salts include what this derivant and alkali were formed
Salt.Such as: alkali metal salt such as Li, Na and K salt；Alkali salt such as Ca and Mg salt；Organic alkali salt, as lysine, arginine,
Guanidine, diethanolamine, choline, trometamol etc.；Ammonium or substituted ammonium salt and aluminium salt.The hydration number of described hydrate is 0
～any real number in 16.These salt and prodrug forms can each dissociate structure above compound.
Currently preferred part of compounds structure and name are as follows:
Compound 1
2-(3-cyano group-4-positive propoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 2
2-(3-cyano group-4-isopropyl phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 3
2-(3-cyano group-4-n-butoxyphenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 4
2-(3-cyano-4-isobutoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 5
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 6
2-(3-cyano group-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 7
2-(3-cyano group-4-benzyloxy-phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 8
2-(3-cyano group-4-allyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 9
2-(3-nitro-4-positive propoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 10
2-(3-nitro-4-isopropyl phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 11
2-(3-nitro-4-n-butoxyphenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 12
2-(3-nitro-4-isobutoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 13
2-(3-nitro-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 14
2-(3-nitro-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 15
2-(3-nitro-4-benzyloxy-phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 16
2-(3-nitro-4-allyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-carboxylic acid compounds 17
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compound 18
2-(3-cyano group-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compound 21
2-(3-nitro-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compound 22
2-(3-nitro-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine
2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid of the present invention according to
Route I synthesis obtains:
So that 4-oxyl-3-cyano group/as raw material, (synthetic method sees Applied Organometallic to nitro-analine
Chemistry,29(2015),683-689；US5854245,29 (1998)), anti-through diazotising, condensation, ring-closure reaction, hydrolysis
Should, obtain 2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid compound.
2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formyl hydrazine of the present invention
Compound obtains according to route II synthesis.
With 2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-Ethyl formate class chemical combination
Thing obtains 2-(3-nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compounds through hydrazinolysis.
2-provided by the present invention (3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-first
Acid or the preparation of 2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compounds
Method simple possible, yield is preferable.
2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid and 2-(3-cyano group/
Nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compounds have preferable xanthine oxidation
Enzyme inhibition, can be used for preparing gout, antihyperuricemic disease drug.
Detailed description of the invention
Be will assist in by following example and understand the present invention, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resoance spectrum is by AVANCE-400/600, Bruker ARX-300 Fourier
Leaf transformation nuclear magnetic resonance chemical analyser measures, and mass spectrum is by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrum
Instrument measures.
Embodiment 1:2-(3-cyano group-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 1) preparation
(1) diazotising and condensation:
By 5-amino-2-positive propoxy benzonitrile (0.48g, 2.6mmol) crude product, 15%HCl solution (5mL), add extremely
H2In O (5mL), stir 30 minutes under condition of ice bath；NaNO it is slowly added dropwise in system2The aqueous solution of (0.27g, 3.0mmol),
Dripping and finish, ice bath continues reaction 30 minutes；In system, add the ethanol solution of ethyl acetoacetate (0.39g, 3mmol), then use
System pH is adjusted to neutrality by the saturated aqueous solution of sodium acetate, reacts 30 minutes；Separating out yellow solid, sucking filtration, filter cake is washed, and is dried
Obtain 2-(3-cyano group-4-positive propoxy benzhydrazon)-ethyl 3-oxobutanoate crude product, yield 83%.
(2) cyclization:
By 2-(3-cyano group-4-positive propoxy benzhydrazon)-ethyl 3-oxobutanoate crude product (0.2g, 0.63mmol), acetic acid
Ammonium (0.092g, 1.2mmol), copper bromide (0.011g, 0.05mmol) adds molten with the mixing of glacial acetic acid (5mL) to DMF (5mL)
In liquid, it is warming up to 110 DEG C and reacts 5 hours；The system for the treatment of is cooled to room temperature, is poured into by reactant liquor in water (20mL), uses ethyl acetate
(10mL) it is extracted twice, organic layer brine It；Decompression removes organic solvent, is dried, and solid obtains 2-through column chromatography purification
(3-cyano group-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-Ethyl formate, yield 85%.
(3) hydrolysis:
By 2-(3-cyano group-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-Ethyl formate (0.1g,
0.3mmol), 1M NaOH solution (5mL), add to ethanol (5mL), 45 DEG C are reacted 2 hours；It is organic molten that decompression removes part
Agent, adds water (5mL), then with 1M HCl solution, system pH is adjusted to faintly acid, separate out white solid, sucking filtration, wash filter cake, dry
Dry；Solid obtains 2-(3-cyano group-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-first through column chromatography purification
Acid, yield 90%.
2-(3-cyano group-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 1) total
Yield is 63% (in terms of raw material 4-positive propoxy-3-cyano-aniline), its structural formula,1H-NMR and MS data are listed in the table below-1
In.
Embodiment 2:2-(3-cyano group-4-isopropyl phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 2) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-isopropoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 2), total recovery is 68% (with raw material 4-isopropoxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 3:2-(3-cyano group-4-n-butoxyphenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 3) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-positive propoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 3), total recovery is 69% (with raw material 4-n-butoxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 4:2-(3-cyano-4-isobutoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 4) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-isopropoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 4), total recovery is 63% (with raw material 4-isobutoxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 5:2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 5) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-n-pentyloxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 5), total recovery is 76% (with raw material 4-n-pentyloxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 6:2-(3-cyano group-4-isoamoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 6) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-isoamyl phenyl ether with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 6), total recovery is 65% (with raw material 4-isoamoxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 7:2-(3-cyano group-4-benzyloxy-phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound
7) preparation
In addition to using different raw material, with the method that embodiment 1 is identical prepare 2-(3-cyano group-4-benzyloxy-phenyl)-
5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 7), total recovery is 64% (with raw material 4-benzyloxy-3-cyano group benzene
Amine meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 8:2-(3-cyano group-4-allyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 8) preparation
In addition to using different raw materials, prepare 2-(3-cyano group-4-allyloxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 8), total recovery is 65% (with raw material 4-allyloxy-3-
Cyano-aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 9:2-(3-nitro-4-positive propoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 9) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-positive propoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 9), total recovery is 67% (with raw material 4-positive propoxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 10:2-(3-nitro-4-isopropyl phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (is changed
Compound 10) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-isopropoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 10), total recovery is 69% (with raw material 4-isopropoxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 11:2-(3-nitro-4-n-butoxyphenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (is changed
Compound 11) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-n-butoxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 11), total recovery is 66% (with raw material 4-n-butoxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 12:2-(3-nitro-4-isobutoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (is changed
Compound 12) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-isobutyl phenyl ether with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 12), total recovery is 71% (with raw material 4-isobutoxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 13:2-(3-nitro-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (is changed
Compound 13) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-n-pentyloxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 13), total recovery is 65% (with raw material 4-n-pentyloxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 14:2-(3-nitro-4-isoamoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (is changed
Compound 14) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-n-pentyloxy benzene with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 14), total recovery is 73% (with raw material 4-isoamoxy-3-
Nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 15:2-(3-nitro-4-benzyloxy-phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 15) preparation
In addition to using different raw materials, prepare 2-(3-nitro-4-isoamyl phenyl ether with the method that embodiment 1 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 15), total recovery is 67% (with raw material 4-benzyloxy-3-nitre
Base aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 16:2-(3-nitro-4-benzyloxy-phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formic acid (chemical combination
Thing 16) preparation
In addition to using different raw material, with the method that embodiment 1 is identical prepare 2-(3-nitro-4-benzyloxy-phenyl)-
5-methyl-2H-1,2,3 ,-triazole-4-formic acid (compound 16), total recovery is 69% (with raw material 4-allyloxy-3-nitro
Aniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 17:2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine
The preparation of (compound 17)
2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 is prepared with the method that embodiment 1 is identical ,-three
Nitrogen azoles-4-Ethyl formate, then react to obtain 2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-three nitrogen through hydrazinolysis
Azoles-4-formylhydrazine (compound 17).
By 2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-Ethyl formate (0.12g,
0.3mmol), 80% hydrazine hydrate (0.3mL), add to ethanol (5mL), 55 DEG C are reacted 8 hours；Removal of solvent under reduced pressure, solid
2-(3-cyano group-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine (chemical combination is obtained through column chromatography purification
Thing 17), total recovery is 60% (in terms of raw material 4-n-pentyloxy-3-nitroaniline), its structural formula,1H-NMR and MS data are listed in
In following table-1.
Embodiment 18:2-(3-cyano group-4-isoamoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine
The preparation of (compound 18)
In addition to using different raw materials, prepare 2-(3-cyano group-4-isoamyl phenyl ether with the method that embodiment 17 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine (compound 18), total recovery be 59% (with raw material 4-isoamoxy-
3-nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 19:2-(3-nitro-4-n-pentyloxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine
The preparation of (compound 19)
In addition to using different raw materials, prepare 2-(3-nitro-4-n-pentyloxy benzene with the method that embodiment 17 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine (compound 19), total recovery be 70% (with raw material 4-n-pentyloxy-
3-nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 20:2-(3-nitro-4-isoamoxy phenyl)-5-methyl-2H-1,2,3 ,-triazole-4-Ethyl formate
The preparation of (compound 20)
In addition to using different raw materials, prepare 2-(3-cyano group-4-isoamyl phenyl ether with the method that embodiment 17 is identical
Base)-5-methyl-2H-1,2,3 ,-triazole-4-formylhydrazine (compound 20), total recovery be 62% (with raw material 4-isoamoxy-
3-nitroaniline meter), its structural formula,1H-NMR and MS data are listed in the table below in-1.
Embodiment 21: the external pharmacology test of the compound of the present invention
(1) experimental principle:
It is substrate detection XOD (purchased from SIGMA) activity with xanthine (purchased from SIGMA).Observe sample the activity of enzyme is pressed down
System, to evaluate the inhibition of sample.The positive reference compound used is allopurinol (allopurinol).
(2) external activity method of testing and result:
Containing appropriate XOD, pH 7.4 phosphate buffer, xanthine (purchased from SIGMA) kindly product in 200 μ L reaction systems, with
Time set up blank (without enzyme and sample) and negative control (without sample), sample concentration is 10 μm ol L-1, 25 DEG C anti-
Answering 90 minutes, 293nM measures OD value, calculates suppression ratio according to equation below, and the suppression ratio value of each compound is shown in Table-2.
Table-1
Table-2
Claims (10)
1. such as a compounds of formula I, its pharmaceutically acceptable salt, hydrate or dissolved matter:
Wherein: X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C10Alkyl, C3-C10
Allylic alkylation, C3-C10Alkynes alkyl, C4-C7Cycloalkyl-alkyl, C7-C10Aryl alkyl.
Compound the most according to claim 1, its pharmaceutically acceptable salt, hydrate or solvate, its feature exists
In: X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C8Alkyl, C3-C8Allylic alkylation,
C3-C8Alkynes alkyl, C4-C6Cycloalkyl-alkyl, C7-C9Aryl alkyl.
Compound the most according to claim 1, its pharmaceutically acceptable salt, hydrate or solvate, its feature exists
In: X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R is the C of straight or branched1-C6Alkyl, C3-C6Allylic alkylation,
C3-C6Alkynes alkyl, C4-C6Cycloalkyl-alkyl, C7-C9Aryl alkyl.
Compound the most according to claim 1, its pharmaceutically acceptable salt, hydrate or solvate, its feature exists
In: X is hydroxy-acid group or formylhydrazine group；Y is cyano group or nitro；R be ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group,
The tert-butyl group, n-pentyl, isopentyl, tertiary amyl, benzyl, pi-allyl.
5. according to the compound described in claim 1-4 any one, its pharmaceutically acceptable salt, hydrate or solvation
Thing, it is characterised in that: the salt that described salt is formed by this compound and alkali；The hydration number of described hydrate is 0～16
In any real number.
Compound the most according to claim 5, its pharmaceutically acceptable salt, hydrate or solvate, its feature exists
In: wherein said salt is alkali metal salt, alkali salt or organic alkali salt, and described alkali metal salt is Li, Na or K salt, institute
The alkali salt stated is Ca or Mg salt, and described organic alkali salt is lysine, arginine, guanidine, diethanolamine, choline or ammonia fourth
The salt of triol, ammonium or substituted ammonium salt and aluminium salt.
7. the compound described in claim 1-6 any one, pharmaceutically acceptable salt, hydrate or solvate, it is selected from:
2-(3-cyano group-4-positive propoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-isopropyl phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-n-butoxyphenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano-4-isobutoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-benzyloxy-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-allyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-positive propoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-isopropyl phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-n-butoxyphenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-isobutoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-benzyloxy-phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-nitro-4-allyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formic acid
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine
2-(3-cyano group-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine
2-(3-nitro-4-n-pentyloxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine
2-(3-nitro-4-isoamoxy phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine.
8. a pharmaceutical composition, comprises the compound described in claim 1-7 any one, its pharmaceutically acceptable salt,
Hydrate or solvate and pharmaceutically acceptable carrier.
9. the preparation method of a compound as claimed in claim 1, it is characterised in that: with 4-oxyl-3-cyano group/nitre
Base-aniline is raw material, through diazotising, condensation, ring-closure reaction, hydrolysis, obtain 2-(3-cyano group/nitro-4-substituted-phenyl)-
4-methyl-2H-1,2,3-triazole-4-formic acid compound；
With 2-(3-cyano group/nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-Ethyl formate compounds it is
Raw material, obtains 2-(3-nitro-4-substituted-phenyl)-4-methyl-2H-1,2,3-triazole-4-formylhydrazine compounds through hydrazinolysis.
10. compound, its pharmaceutically acceptable salt, hydrate or solvate described in claim 1-7 any one or
The application in preparing gout, inhibiting hyperuricemia medicine of the compositions described in claim 8.
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