CN103936693A - 2-(3-cyano-4-substituted phenyl)-4-methyl-1, 3-selenazole-5-formic acid and formate compounds and preparation method thereof - Google Patents
2-(3-cyano-4-substituted phenyl)-4-methyl-1, 3-selenazole-5-formic acid and formate compounds and preparation method thereof Download PDFInfo
- Publication number
- CN103936693A CN103936693A CN201310022624.9A CN201310022624A CN103936693A CN 103936693 A CN103936693 A CN 103936693A CN 201310022624 A CN201310022624 A CN 201310022624A CN 103936693 A CN103936693 A CN 103936693A
- Authority
- CN
- China
- Prior art keywords
- selenazoles
- methyl isophthalic
- cyano group
- isophthalic acid
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/02—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms not condensed with other rings
- C07D293/04—Five-membered rings
- C07D293/06—Selenazoles; Hydrogenated selenazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, relates to 2-(3-cyano-4-substituted phenyl)-4-methyl-1, 3-selenazole-5-formic acid and formate compounds, pharmaceutically acceptable salts, pharmaceutically acceptable solvates which have xanthine oxidase inhibitory activity and have the general formula of I, and a preparation method thereof, and also relates to use of the compounds in preparation of drugs for treating hyperuricemia and gout diseases. The formula I is shown in the specification, R and R' independently are H; or R and R' independently are straight chain or branched chain C1-C10 alkyl, C3-C10 ene alkyl, C3-C10 alkyne alkyl, C4-C7 naphthenic alkyl, and C7-C10 aryl alkyl.
Description
Technical field
The invention belongs to medical technical field, relate to 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester compound and preparation method, be specifically related to 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester compound thereof, pharmaceutically useful salt, pharmaceutically useful solvate and preparation method thereof, and the purposes of these compounds in medicine.
Background technology
Gout is a kind of global metabolic disease, and the height of its morbidity is subject to the impact of the many factors such as economic development level, environment, food habits, race, heredity, medical level, Case definition and statistical method, so various countries' report differs greatly.Show according to available data, European and American areas prevalence of hyperuricemia is about 2% ~ 18%, and the morbidity of gout is 0.2% ~ 1.7%.The indigenous Serum Uric Acid Level of the South Pacific is up to 64%.Japan, after World War II, along with the variation of dietary structure, takes in increasing of animal proteinum and fat, and hyperuricemia and patient with gout have and significantly increase trend, infer that prevalence of gout was is 0.5%.In a word, no matter be in American-European countries or in countries in Asia, the morbidity of gout has the trend increasing year by year, also ascendant trend linearly of the morbidity of China's hyperuricemia and gout.There is in recent years statistics to show, be about 0.84% in the total morbidity of all age bracket gouts.
Gout is that uric acid is accumulated in vivo owing to producing uric acid in body too much and the decline of kidney removing ability, causes urate crystal in joint and each internal organs precipitation.Clinical treatment gout medicine is mainly divided into promotion uric acid excretion and suppresses uricogenesis at present, and adopts adequate measure to improve relevant symptoms.Along with the raising of living standards of the people, be mainly that the proportion of various animal foods in dietary structure increases gradually, original rare prevalence of gout was and day Ju are increased.How to develop a kind of effectively, the medicine of safety and easy administration become to continue a problem solving.In decades, HPPIsopurind be clinically unique one for suppressing the medicine of uricogenesis, and be widely used in clinical as the gold medicine of gout, but need to repeat heavy dose of administration and maintain higher levels of drugs, cause the serious even fatal untoward reaction due to drug accumulation simultaneously.How to develop a kind of effectively, the medicine of safety and easy administration become to continue a problem solving.The disappearance of medicine, brings huge commercial opportunities to the exploitation of newtype drug.
Febuxostat (febuxostat) is first disclosed as in WO9209279A1, for xanthine oxidase inhibitor of new generation, be used for the treatment of clinically the too high disease of uric acid (gout), this medicine is that Japanese Teijin Ltd (Teijin) went on the market in Japanese publication 2004 beginning of the years, and go on the market its end of the year at U. S. application; IPSEN company is in Europe application listing, and European Union ratifies its listing in May, 2008.
2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester compound thereof have not yet to see report as the research of xanthine oxidase inhibitor.
Summary of the invention
The object of the invention is to design, synthetic 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid with good xanthine oxidase inhibitory activity, 3-selenazoles-5-formic acid and ester compound thereof; Prepared compound shows good XOD restraining effect in vitro, can be used for preparation treatment hyperuricemia and goat medicine.
The general structure of compound of the present invention is as follows:
Wherein: R and R' are independently H respectively separately; Or R and R' independent separately be respectively the C of straight or branched
1-C
10alkyl, C
3-C
10allylic alkylation, C
3-C
10alkynes alkyl, C
3-C
7cycloalkylalkyl, C
7-C
10arylalkyl.
Preferably, R and R' are independently H separately; Or R and R' are independently the C of straight or branched separately
1-C
8alkyl, C
3-C
8allylic alkylation, C
3-C
8alkynes alkyl, C
3-C
6cycloalkylalkyl, C
7-C
9arylalkyl.
More preferably, R and R' are independently H separately; Or R and R' are independently the C of straight or branched separately
1-C
5alkyl, C
3-C
5allylic alkylation, C
3-C
5alkynes alkyl, C
3-C
6cycloalkylalkyl, C
7-C
9arylalkyl.
Most preferably, R and R' are independently H, methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, ring the third methyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, tertiary amyl, allyl group, propargyl, benzyl separately.
Compound of the present invention also comprises pharmaceutically acceptable non-toxic salt and hydrate or other prodrug forms that shown in said structure formula, derivative forms, and these pharmaceutically acceptable non-toxic salt comprise the salt that this derivative and alkali form.For example: an alkali metal salt is as Li, Na and K salt; Alkaline earth salt is as Ca and Mg salt; Organic alkali salt, as Methionin, arginine, guanidine, diethanolamine, choline, Trometamol etc.; The ammonium salt of ammonium or replacement and aluminium salt.The hydration number of described hydrate is any real number in 0～16.These salt and the prodrug forms said structure formula compound that can dissociate separately.
The preferred part of compounds structure of the present invention and name are as follows:
Compound 1
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 2
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 3
2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 4
2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 5
2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 6
2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 7
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 8
2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 9
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 10
2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 11
2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 12
2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 13
2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
Compound 14
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 15
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 16
2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 17
2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 18
2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 19
2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 20
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 21
2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 22
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 23
2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 24
2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 25
2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 26
2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
Compound 27
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-benzyl formate.
2-of the present invention (3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid compounds obtains according to route I is synthetic:
Taking p-HBN as raw material, through addition, cyclization, formylation, cyano group, alkylation and hydrolysis reaction, obtain 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid compounds.
2-of the present invention (3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic ether compounds synthesizes and obtains according to route I or route II.
Route I, taking p-HBN as raw material, through addition, cyclization, formylation, cyano group and alkylated reaction, obtains 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic ether compounds.
Route II is by 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid compounds and corresponding halides (R'X) are through alkylated reaction, obtain 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic ether compounds.
2-provided by the present invention (3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, preparation method's simple possible of 3-selenazoles-5-formic acid and ester compound thereof, yield is better.
2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester compound thereof have good XOD restraining effect, can be used for preparing antigout, antihyperuricemic disease drug.
Embodiment
To contribute to understand the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, Bruker ARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrograph.
embodiment 1:2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 1)
(1) addition: 0.79 g selenium powder (10 mmol) mixes with 0.46 g sodium borohydride (12 mmol), system is inflated with nitrogen protection after vacuumizing; Under ice bath, add 20 mL dehydrated alcohols, make sodium hydrogen selenide solution; Add p-HBN 1.2 g(10 mmol), back flow reaction 6 h; Drip 6 M HCl solution and make system become acid, continue reaction 1 h; Add 100 mL H
2o, ice bath stirs 0.5 h, filters, and after being dried, obtains 4-hydroxyl seleno benzamide crude product, yield 60%.Crude product is not purified is directly used in next step reaction.
(2) cyclization: 2.0 g(10 mmol) 5 mL ethanolic solns of 4-hydroxyl seleno benzamide crude product, stirring heating refluxes, and drips 2-chloroacetyl acetacetic ester 1.65 g(10 mmol), drip off rear continuation 4 h that reflux; Cooling rear suction filtration, obtains 2-(4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product, yield 73% after drying.Crude product is not purified is directly used in next step reaction.
(3) formylation: 2-(4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 1.0 g(3.215 mmol) be dissolved in 10 mL anhydrous acetonitriles, under stirring, add Magnesium Chloride Anhydrous 0.46 g(4.823 mmol), add paraformaldehyde 0.68 g in batches, drip 1.7 mL triethylamines, be heated to reflux, reaction 6 h; After slightly cold, pour quencher reaction in suitable quantity of water into, it is 5.0 ~ 6.0 that dilute hydrochloric acid is adjusted pH, adds large water gaging, and the cooling product of separating out filters, and after being dried, obtains crude product, yield 75%.Crude product is not purified is directly used in next step reaction.
(4) cyano group: 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 500 mg(1.475 mmol), oxammonium hydrochloride 102 mg(1.475 mmol), sodium formiate 100 mg(1.475 mmol) mix with 5 mL anhydrous formic acids, be heated with stirring to backflow, reaction 5 h; Cooling, suction filtration, solid water is washed till neutrality, after being dried, obtains 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, and 3-selenazoles-5-ethyl formate obtains crude product, yield 72%.Crude product is not purified is directly used in next step reaction.
(5) hydrolysis: 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 336 mg(1 mmol) mix with 2 mL ethanol and 1mL tetrahydrofuran (THF), be stirred to entirely molten; Drip 1M sodium hydroxide solution 0.1 mL, heating reflux reaction 1 h; Decompression steams organic solvent, adds 65 mL ethyl acetate, under stirring, adjusts pH as 2.0 ~ 3.0 taking 1M hydrochloric acid; Separate organic layer, water layer is extracted with ethyl acetate 2 times, merges organic layer, through washing, anhydrous Na
2sO
4dry, pressure reducing and steaming ethyl acetate, obtains 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid crude product.Crude product obtains 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid (compound 1), yield 80% through recrystallizing methanol.
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, the total recovery of 3-selenazoles-5-formic acid (compound 1) is that 19%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 2:2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 2)
Prepare 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate with the identical method of embodiment 1.
Alkylation: 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 336 mg(1 mmol), salt of wormwood 138 mg(1 mmol), 5 mg potassiumiodides mix with 2 mL DMF, under stirring at room temperature, drip monobromethane 108 mg(1 mmol): reaction solution is heated to 35 DEG C, reaction 8 h; After cooling, pour in quintuple water, separate out solid, suction filtration, filter cake washing, is dried to obtain 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product, yield 83%.Crude product is not purified is directly used in next step reaction.
Hydrolysis: 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 364 mg(1 mmol) mix with 3.6 mL ethanol, be stirred to entirely molten; Drip 1M sodium hydroxide solution 0.1 mL, heating reflux reaction 1 h; Decompression steams organic solvent, adds 65 mL ethyl acetate, under stirring, adjusts pH as 2.0 ~ 3.0 taking 1M hydrochloric acid; Separate organic layer, water layer is extracted with ethyl acetate 2 times, merges organic layer, through washing, anhydrous Na
2sO
4dry, pressure reducing and steaming ethyl acetate, obtains 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid crude product.Crude product obtains 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid (compound 2), yield 78% through recrystallizing methanol.
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, the total recovery of 3-selenazoles-5-formic acid (compound 2) is that 15%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 3:2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 3)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 3), total recovery is that 17%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 4:2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 4)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 4), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 5:2-(3-cyano group-4-ring propoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 5)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-ring propoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 5), total recovery is that 9%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 6: 2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 6)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 6), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 7:2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 7)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 7), total recovery is that 10%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 8:2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 8)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4 sec-butoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 8), total recovery is that 8%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 9: 2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 9)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 9), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 10: 2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 10)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 10), total recovery is that 10%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 11: 2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 11)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 11), total recovery is that 18%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 12: 2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 12)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 12), total recovery is that 16%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 13: 2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-formic acid (compound 13)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 2,3-selenazoles-5-formic acid (compound 13), total recovery is that 18%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 14:2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 14)
(1) addition: 0.79 g selenium powder (10 mmol) mixes with 0.46 g sodium borohydride (12 mmol), system is inflated with nitrogen protection after vacuumizing; Under ice bath, add 20 mL dehydrated alcohols, make sodium hydrogen selenide solution; Add p-HBN 1.2 g(10 mmol), back flow reaction 6 h; Drip 6 M HCl solution and make system become acid, continue reaction 1 h; Add 100 mL H
2o, ice bath stirs 0.5 h, filters, and after being dried, obtains 4-hydroxyl seleno benzamide crude product, yield 60%.Crude product is not purified is directly used in next step reaction.
(2) cyclization: 2.0 g(10 mmol) 5 mL ethanolic solns of 4-hydroxyl seleno benzamide crude product, stirring heating refluxes, and drips 2-chloroacetyl acetacetic ester 1.65 g(10 mmol), drip off rear continuation 4 h that reflux; Cooling rear suction filtration, obtains 2-(4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product, yield 73% after drying.Not purifiedly be directly used in next step reaction.
(3) formylation: 2-(4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 1.0 g(3.215 mmol) be dissolved in 10 mL anhydrous acetonitriles, under stirring, add Magnesium Chloride Anhydrous 0.46 g(4.823 mmol), add paraformaldehyde 0.68 g in batches, drip 1.7 mL triethylamines, be heated to reflux, reaction 6 h; After slightly cold, pour quencher reaction in suitable quantity of water into, it is 5.0 ~ 6.0 that dilute hydrochloric acid is adjusted pH, adds large water gaging, and the cooling product of separating out filters, and after being dried, obtains crude product, yield 75%.Crude product is not purified is directly used in next step reaction.
(4) cyano group: 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 500 mg(1.475 mmol), oxammonium hydrochloride 102 mg(1.475 mmol), two water sodium formiate 100 mg(1.475 mmol) mix with 1.6 mL anhydrous formic acids, be heated with stirring to backflow, reaction 5 h; Cooling, suction filtration, solid water is washed till neutrality, after dry, obtain 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate obtains crude product, and crude product, through column chromatography purification, obtains 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate (compound 14), yield 68%.
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, the total recovery of 3-selenazoles-5-ethyl formate (compound 14) is that 22%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 15:2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 15)
Prepare 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate with the identical method of embodiment 14.
Alkylation: 2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product 336 mg(1 mmol), salt of wormwood 138 mg(1 mmol), 5 mg potassiumiodides mix with 2 mL DMF, under stirring at room temperature, drip monobromethane 108 mg(1 mmol): reaction solution is heated to 70 DEG C, reaction 8 h; After cooling, pour in quintuple water, separate out solid, suction filtration, filter cake washing, is dried to obtain 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate crude product; Crude product, through column chromatography purification, obtains 2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate (compound 15), yield 75%.
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, the total recovery of 3-selenazoles-5-ethyl formate (compound 15) is that 18%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 16:2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 16)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 16), total recovery is that 19%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 17:2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 17)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 17), total recovery is that 15%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 18:2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 18)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 18), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 19: 2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 19)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 19), total recovery is that 14%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 20:2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 20)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 20), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 21:2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 21)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-sec-butoxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 21), total recovery is that 11%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 22: 2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 22)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 22), total recovery is that 15%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 23: 2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 23)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 23), total recovery is that 12%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 24: 2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 24)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 24), total recovery is that 20%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 25: 2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 25)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 25), total recovery is that 19%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 26: 2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-ethyl formate (compound 26)
Except using corresponding alkylating reagent in alkylation one step, prepare 2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid with the identical method of embodiment 15,3-selenazoles-5-ethyl formate (compound 26), total recovery is that 21%(is in raw material p-HBN), its structural formula,
1h-NMR and MS data are listed in the table below in-1.
embodiment 27: 2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, the preparation of 3-selenazoles-5-benzyl formate (compound 27)
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid (compound 7) 364 mg(1 mmol), cylite 413 mg(1.2 mmol), tetrabutyl ammonium fluoride 1.2 mg(1.1 mmol) mix with 5 mL tetrahydrofuran (THF)s, stirring at room temperature is reacted 1 h; Add water, water layer is extracted with ethyl acetate 3 times, merges organic layer, through anhydrous Na
2sO
4dry, concentrating under reduced pressure obtains crude product; Crude product, through column chromatography purification, obtains 2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-benzyl formate (compound 27), yield 85%; 2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, the structural formula of 3-selenazoles-5-benzyl formate (compound 27),
1h-NMR and MS data are listed in the table below in-1.
embodiment 28: the medicine in-vitro test of science of compound of the present invention
(1) experimental principle: detect XOD(taking xanthine (purchased from SIGMA) as substrate purchased from SIGMA) activity.Observe sample the activity of enzyme is suppressed, with the inhibition of assess sample.The positive reference compound adopting is Zyloric (allopurinol).
(2) external activity testing method and result: contain appropriate XOD, pH 7.4 phosphoric acid buffers, the kindly product of xanthine (purchased from SIGMA) in 200 μ L reaction systems, set up blank (not containing enzyme and sample) and negative control (not containing sample), sample concentration is 10 μ molL simultaneously
-1, 25 DEG C of reaction 90 min, 293 nM measure OD value, calculate inhibiting rate according to following formula, and the inhibiting rate value of each compound is in Table-2.
Claims (10)
1. as a compound for general formula I, its pharmacy acceptable salt, hydrate or solvate:
Wherein: R and R' are independently H separately; Or R and R' are independently the C of straight or branched separately
1-C
10alkyl, C
3-C
10allylic alkylation, C
3-C
10alkynes alkyl, C
4-C
7cycloalkylalkyl, C
7-C
10arylalkyl.
2. compound according to claim 1, its pharmacy acceptable salt, hydrate or solvate, is characterized in that: R and R' are independently H separately; Or R and R' are independently the C of straight or branched separately
1-C
8alkyl, C
3-C
8allylic alkylation, C
3-C
8alkynes alkyl, C
4-C
6cycloalkylalkyl, C
7-C
9arylalkyl.
3. compound according to claim 1, its pharmacy acceptable salt, hydrate or solvate, is characterized in that: R and R' are independently H separately; Or R and R' are independently the C of straight or branched separately
1-C
5alkyl, C
3-C
5allylic alkylation, C
3-C
5alkynes alkyl, C
4-C
6cycloalkylalkyl, C
7-C
9arylalkyl.
4. compound according to claim 1, its pharmacy acceptable salt, hydrate or solvate, is characterized in that: R and R' are independently H, methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, ring the third methyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, tertiary amyl, allyl group, propargyl, benzyl separately.
5. compound according to claim 1, its pharmacy acceptable salt, hydrate or solvate, is characterized in that: the salt that described salt forms for this compound and alkali; The hydration number of described hydrate is any real number in 0 ~ 16.
6. compound according to claim 5, its pharmacy acceptable salt, hydrate or solvate, it is characterized in that: wherein said salt is an alkali metal salt, alkaline earth salt or organic alkali salt, described an alkali metal salt is Li, Na or K salt, described alkaline earth salt is Ca or Mg salt, described organic alkali salt is the salt of Methionin, arginine, guanidine, diethanolamine, choline or Trometamol, the ammonium salt of ammonium or replacement and aluminium salt.
7. compound claimed in claim 1, its pharmacy acceptable salt, hydrate or solvate, be selected from:
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid
2-(3-cyano group-4-hydroxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-ethoxyl phenenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-isopropyl phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-encircles the third p-methoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-n-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-sec-butoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-n-pentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-isopentyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-allyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-alkynes propoxy-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano group-4-benzyloxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-ethyl formate
2-(3-cyano-4-isobutoxy phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-benzyl formate.
8. a pharmaceutical composition, comprises compound, its pharmacy acceptable salt, hydrate or solvate and the pharmaceutically acceptable carrier of claim 1-7 described in any one.
9. a preparation method for compound as claimed in claim 1, is characterized in that:
2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, being prepared as follows of 3-selenazoles-5-formic acid compounds:
Obtain crude product taking p-HBN as raw material through addition, cyclization, formylation, cyano group, alkylation and hydrolysis reaction, obtain sterling through recrystallization purifying;
2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, being prepared as follows of 3-selenazoles-5-formic ether compounds:
Obtain crude product taking p-HBN as raw material through addition, cyclization, formylation, cyano group and alkylated reaction, obtain sterling through column chromatography purification; Or with 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid compounds is raw material, obtains crude product through Steglich esterification, obtains sterling through column chromatography purification.
10. compound, its pharmacy acceptable salt, hydrate or the solvate of claim 1-7 described in any one or composition claimed in claim 8 are in the application of preparing in antigout, anti-antihyperuricemic disease drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310022624.9A CN103936693B (en) | 2013-01-22 | 2013-01-22 | 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester type compound thereof and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310022624.9A CN103936693B (en) | 2013-01-22 | 2013-01-22 | 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester type compound thereof and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103936693A true CN103936693A (en) | 2014-07-23 |
| CN103936693B CN103936693B (en) | 2016-06-15 |
Family
ID=51184606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310022624.9A Expired - Fee Related CN103936693B (en) | 2013-01-22 | 2013-01-22 | 2-(3-cyano group-4-substituted-phenyl)-4-methyl isophthalic acid, 3-selenazoles-5-formic acid and ester type compound thereof and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103936693B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484494A (en) * | 2018-06-15 | 2018-09-04 | 沈阳药科大学 | 2- oxo -1,2- dihydropyridine -4- formic acid compounds |
| CN108689948A (en) * | 2018-06-04 | 2018-10-23 | 沈阳药科大学 | 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds and its preparation method and application |
| CN108929275A (en) * | 2018-06-14 | 2018-12-04 | 沈阳药科大学 | 6- (3,4- substituted-phenyl) -3- oxo -2,3- dihydrogen dazin -4- hydrazide kind compound and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) * | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| CN101928259A (en) * | 2009-06-18 | 2010-12-29 | 南京海辰药业有限公司 | 2-arylthiazole derivative and medicament composition thereof |
| CN103130744A (en) * | 2012-08-28 | 2013-06-05 | 沈阳药科大学 | Selenazole formic acid formic acid compound and preparation method and application thereof |
| 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 |
-
2013
- 2013-01-22 CN CN201310022624.9A patent/CN103936693B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) * | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| CN101928259A (en) * | 2009-06-18 | 2010-12-29 | 南京海辰药业有限公司 | 2-arylthiazole derivative and medicament composition thereof |
| CN103130744A (en) * | 2012-08-28 | 2013-06-05 | 沈阳药科大学 | Selenazole formic acid formic acid compound and preparation method and application thereof |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| QI GUAN ET AL.: "Synthesis and bioevaluation of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acids as potent xanthine oxidase inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108689948A (en) * | 2018-06-04 | 2018-10-23 | 沈阳药科大学 | 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds and its preparation method and application |
| CN108689948B (en) * | 2018-06-04 | 2021-08-24 | 沈阳药科大学 | 6- (3, 4-substituted phenyl) -2-mercaptopyrimidine-4-formic acid compound and preparation method and application thereof |
| CN108929275A (en) * | 2018-06-14 | 2018-12-04 | 沈阳药科大学 | 6- (3,4- substituted-phenyl) -3- oxo -2,3- dihydrogen dazin -4- hydrazide kind compound and application thereof |
| CN108929275B (en) * | 2018-06-14 | 2021-08-24 | 沈阳药科大学 | 6- (3, 4-substituted phenyl) -3-oxo-2, 3-dihydropyridazine-4-hydrazide compound and application thereof |
| CN108484494A (en) * | 2018-06-15 | 2018-09-04 | 沈阳药科大学 | 2- oxo -1,2- dihydropyridine -4- formic acid compounds |
| CN108484494B (en) * | 2018-06-15 | 2021-07-30 | 沈阳药科大学 | 2-oxo-1, 2-dihydropyridine-4-carboxylic acid compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103936693B (en) | 2016-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210017163A1 (en) | Hydrochloride salt form for ezh2 inhibition | |
| CN102292316A (en) | Glucagon antagonists | |
| CN100497337C (en) | Folacin dimethylbiguanide and process for production thereof | |
| CN104024213A (en) | Synthetic epigallocatechin gallafe (EGGG) analogs | |
| CN106831735A (en) | It is a kind of to treat heterocyclic compound of osteoporosis and its production and use | |
| US11903907B2 (en) | Soluble honokiol derivatives | |
| CN103936693A (en) | 2-(3-cyano-4-substituted phenyl)-4-methyl-1, 3-selenazole-5-formic acid and formate compounds and preparation method thereof | |
| CN106146419A (en) | Xanthine oxidase inhibitor | |
| EP0236929B1 (en) | 1,2-dithiol-3-thione derivatives, a process for preparing them and a pharmaceutical composition containing them | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CN107001276B (en) | Sodium salt of uric acid transport protein inhibitor and crystal form thereof | |
| CN103145636A (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| JP5932827B2 (en) | Thiazoleamine derivatives and their use as anti-picornavirus infectious agents | |
| EP3964514A1 (en) | Ginkgolide b derivative and salt thereof, preparation method therefor and use thereof | |
| CN112574160B (en) | Galangin derivative and preparation method and application thereof | |
| CN107619428B (en) | Acylated derivative of ornithine and aspartate dipeptide compound and application thereof | |
| CN112430221A (en) | Compound for preventing, treating or relieving hyperuricemia or gout and application thereof | |
| WO2009134847A1 (en) | Prolyl hydroxylase inhibitors | |
| CN106220582B (en) | n, 4-diaryl thiazole-2-amine compound and application thereof as tumor cell proliferation inhibitor | |
| KR20080022940A (en) | Preparation method of triethylene tetramine dihydrochloride | |
| US11845743B1 (en) | Pyrazolidinedione derivatives and their use as PPAR-gamma inhibitors | |
| CN104418822A (en) | Compound with xanthine oxidase inhibition activity, and use thereof | |
| JP2022546958A (en) | MAGL inhibitors and methods of making and using the same | |
| CN105884764B (en) | Novel 8,10- removes diaza-N5Application of the acyl group tetrahydrofolic acid class compound as anti-tumor drug | |
| CN115385854A (en) | Preparation and application of quinoline sulfydryl acetate sulfonamide derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160615 Termination date: 20210122 |