CN104710374A - New compound for gout and preparation method thereof, and application and pharmaceutical preparation of new compound - Google Patents
New compound for gout and preparation method thereof, and application and pharmaceutical preparation of new compound Download PDFInfo
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- CN104710374A CN104710374A CN201510173070.1A CN201510173070A CN104710374A CN 104710374 A CN104710374 A CN 104710374A CN 201510173070 A CN201510173070 A CN 201510173070A CN 104710374 A CN104710374 A CN 104710374A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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Abstract
The invention relates to a new compound lesinurad hydroxamate disclosed as Formula I and a preparation method thereof, a pharmaceutical composition and preparation containing the new compound, and application of the new compound in drug preparation. The preparation method is implemented by reacting lesinurad methyl ester under the action of hydroxylamine hydrochloride. The method has the advantages of accessible raw materials, mild reaction conditions, high product yield and high product purity, and is simple to operate. The new compound has specific therapeutic actions on hyperuricemia, gout, arthritis and gouty arthritis, has the characteristics of high efficiency, low toxicity and high metabolism stability, and has wide application prospects.
Description
Technical field
The present invention relates to medicine, be specifically related to lesinurad of new compound hydroxamic acid shown in a kind of formula I and preparation method thereof and the pharmaceutical composition containing this new compound and its as therapeutical agent particularly as the purposes in hyperuricemia and gout medicine.
Background technology
The serum uric acid level that gout is purine metabolic disturbance and (or) underexcretion and causes raises, a kind of metabolic disease of monosodium urate salt crystal caused by the depositions such as joint, cartilage and kidney.Its main manifestations be repeated relapsing joint red, swollen, hot, pain and dysfunction, even joint deformity, nephrolithiasis and urate nephropathy.And underexcretion or generation increase the Etiological that caused hyperuricemia is gout.
In recent years, the morbidity of gout and hyperuricemia rises year by year.Epidemiological study shows, U.S. adults prevalence of gout is 3.9%, has an appointment 8,300,000 patient with gout in the whole America.In China, the morbidity of adult's hyperuricemia is 8.4%, and the male sex is higher than women, is respectively 9.9%, 7.0%; City resident, apparently higher than urban residents, is respectively 14.9%, 6.6%; The area that per capita gross domestic product's level is higher, prevalence of hyperuricemia is also higher.
Hyperuricemia is not only the direct inducement of gout, also closely related with metabolism syndrome, 2 patients with type Ⅰ DM, hypertension, cardiovascular disorder, chronic nephropathy etc.
At present, the medicine for anti-hyperuricemia mainly contains 3 large classes: xanthine oxidase inhibitor, urate Anion exchanger 1(URAT1) inhibitor and urico-oxidase.
Xanthine oxidase inhibitor is using XOD as target spot, by suppressing its effect to reduce uricogenesis, thus effectively reduces serum uric acid level.It is clinical represents that medicine is Zyloric, Febuxostat and holder take charge of him.
Urico-oxidase a kind ofly directly can be oxidized by uric acid and be decomposed into the oxydase of the wallantoin of solubility, is present in most mammalian body, but do not exist in mankind's body.Wallantoin is a kind of inertia and water-soluble purine metabolism thing, is easy to excretion, mainly through renal excretion.Owing to lacking urico-oxidase in human body, as Mammals, uric acid can not be eliminated by rapid oxidation.Thus, serum uric acid level in body can be reduced by introducing exogenous urico-oxidase.Research display, urico-oxidase can accelerate tophaceous dissolving, can be used for treating the patient with gout that other uric acid resistings are failed to respond to any medical treatment or avoided.The clinical medicine that represents has rasburicase, Pei Geluo enzyme etc.
URAT1 is an important kidney urate transporter, is mainly positioned at the epithelial cell brush border of renal cortex proximal convoluted tubule, and main participation uric acid is in the heavily absorption of kidney proximal tubule.URAT1 transgenation will cause Hypouricemia, and URAT1 knock out mice also shows uric acid eliminating increase and Hypouricemia, and prompting URAT1 is the important translocator of kidney uric acid metabolism.URAT1 inhibitor, by suppressing kidney URAT1 to uric acid Reabsorption, increases uric acid excretion, controls the Be very effective of serum uric acid level.Clinical representative medicine be benzbromarone and probenecid, the two medicine abroad because side effect is rejected use, but uses commonplace at home.
Lesinurad(RDEA-594) be a kind of novel URAT-1 inhibitor, be the meta-bolites of compound R DEA-806, researched and developed by Ardea company.Astrazeneca AB obtains this medicine in cost in 2012 12.6 hundred million dollars of purchase Ardea companies.Astrazeneca AB also developed the compound preparation of lesinurad and Zyloric simultaneously, has also entered III phase clinical study at present.Alone or the associating xanthine oxidase inhibitor of lesinurad all effectively can reduce serum Uric Acid Concentration, and can be used for the patient treating Zyloric not intolerant patient or unsatisfactory curative effect, and response rate even can be made during drug combination to bring up to 90%.Research display, Zyloric unsatisfactory curative effect patient, adopt the curative effect of Zyloric+lesinurad to be better than Zyloric+Febustat, response rate can reach 86%, 41% respectively.
The basic condition of Lesinuard is as follows:
Popular name: lesinuard.
Another name: RDEA594.
Chemical name: 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl] sodium-acetate.
CAS：878672-00-5。
Molecular formula: C
17h
14brN
3o
2s.
Relative molecular mass: 404.28.
Yuan Yan company: Ardea Biosciences.
Structural formula:
Due to lesinuard tachytrophism in vivo, we are by structure of modification, use Molecular Simulation Technique to modify out clinical alternative excellent compounds, therefore, develop a kind of novel URAT-1 inhibitor, have broad application prospects.
Summary of the invention
The object of this invention is to provide the hydroxamic acid lesinurad that a kind of new compound has pharmaceutical use, chemical name is 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl]-N-hydroxyl acetamide, its preparation method and containing the pharmaceutical composition of this new compound and its as therapeutical agent particularly as the purposes in hyperuricemia and gout medicine.
Specifically, the invention provides a kind of new compound hydroxamic acid lesinurad, chemical name is 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl]-N-hydroxyl acetamide, its structural formula is such as formula shown in I:
Present invention also offers the preparation method of a kind of new compound hydroxamic acid lesinurad, its technological line is as follows:
Wherein, step 4 is synthesized 4-cyclopropyl-1-naphthalenylisothiocyanate and is adopted dithiocarbonic anhydride-organic bases-SULPHURYL CHLORIDE decomposition method system, and described organic bases is diethylene diamine, 4-pyridyl pyridine or triethylamine, particularly preferably diethylene diamine; Described SULPHURYL CHLORIDE is methylsulfonyl chloride or toluene sulfonyl chloride, particularly preferably toluene sulfonyl chloride.
Wherein, step 9 is synthesized new compound hydroxamic acid lesinurad and is adopted phase transfer catalysis process, and phase-transfer catalyst selects tetrabutylammonium chloride, benzyltriethylammoinium chloride, hexaoxacyclooctadecane-6, Macrogol 4000, preferred tetrabutylammonium chloride; Step 9 synthesizes each feed ratio ratio of new compound hydroxamic acid lesinurad, lesinurad methyl esters: oxammonium hydrochloride: mass concentration is 25% ~ 42% aqueous solution: tetrabutylammonium chloride is 1:1.1 ~ 1.2:2.5 ~ 3.5:0.02 ~ 0.1; Temperature of reaction is 15 ~ 30 DEG C.
The invention provides a kind of clinical preparation of aforementioned pharmaceutical compositions, clinical preparation provided by the invention is oral preparations.
Use compound of the present invention and composition by oral route, the clinical stage of the dosage used visual age, disease and degree, or the inherited genetic factors of individuality, position, weight, the kind of simultaneously treating, the character of pathology or malignant condition and determining.Can the oral form such as capsule, tablet, solution, suspension, soft capsule.
Special consideration, available newly the present invention is based on new compound hydroxamic acid lesinurad pharmaceutical compositions.At this point, pharmaceutical composition contains compounds of the present invention and pharmaceutically acceptable carrier.Persons skilled in the art do not need to test dosage and the approach that can determine to use compound of the present invention or derivative.
Of the present invention again again an object be to provide the purposes of real a kind of new compound hydroxamic acid lesinurad pharmaceutical compositions in preparation treatment hyperuricemia and gout medicine.
Preparation method of the present invention is simple, and the new compound of preparation effectively can reduce serum Uric Acid Concentration, and has internal metabolism stability.
Embodiment
The following examples can conduct further description the present invention, but these embodiments should as limitation of the scope of the invention.
embodiment 1:the preparation of 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl]-N-hydroxyl acetamide
Technological line is as follows:
1) preparation of 1-cyclopropyl naphthalene
To in the 5L round-bottomed flask of drying, add 1-bromonaphthalene (414.0 g, 2mol), [1, two (diphenylphosphino) propane of 3-] nickelous chloride (165 g, the THF of 0.4mol) He 1500 mL dryings, ice-water bath cooling is lower stirs, in system, slowly drip THF solution 3000 mL of 1.0 mol/L cyclopropyl magnesium bromides with constant pressure funnel.After dropwising, compound of reaction is stirring at room temperature 8h under nitrogen protection, is then warming up to backflow, reaction 36h.After having reacted, reaction mixture is cooled to room temperature, is then carefully poured onto in the frozen water of 10L stirring, stirs, with concentrated hydrochloric acid adjust pH to 2, and CH
2cl
2(4000 mL × 3) extract.Merge organic phase, with 3000 mL 5% sodium chloride solution washings, anhydrous Na
2sO
4dry.Rotary Evaporators boils off solvent, and the resistates obtained joins in 5L normal hexane and 10L toluene, vigorous stirring 1h, and stratification, discards organic layer, obtains colourless liquid 313g, yield 87.2%.
2) preparation of 1-cyclopropyl-4-nitro-naphthalene
In the reactor of 10L, add 1-cyclopropyl naphthalene (253 g, 1.5mol) and 3000mL Glacial acetic acid, ice-water bath cooling is lower stirs, and slowly drips 500mL concentrated nitric acid.After dropwising, reaction mixture at room temperature continues to stir 7h.After having reacted, reaction mixture is poured onto in the frozen water of 6L stirring, continues to stir 20min, CH
2cl
2(1000mL × 3) extract.Merge organic phase, use saturated NaHCO
3solution washing is greater than 7 to aqueous phase pH value, then washs with the sodium chloride solution of 1500 mL 5%, anhydrous Na
2sO
4drying, Rotary Evaporators boils off solvent, and the resistates obtained joins in 3L normal hexane and 4L dimethylbenzene, vigorous stirring 1h, and stratification, discards organic layer, obtains weak yellow liquid 284g, yield 85.9%.
3) preparation of 1-amino-4-cyclopropyl naphthalene
1-cyclopropyl-4-nitro-naphthalene (260 g, 1.21mol), zinc powder (790 g, 12.1 mol), NH is added in the reactor of 10L
4cl(650 g, 12.1mol), 3500mL THF and 1000mL water, stir under reflux.Reaction 10h.After having reacted, reaction mixture cool to room temperature, suction filtration removing solid, filtrate is poured onto in the frozen water of 8L, continues to stir, 20min, CH
2cl
2(2500mL × 3) extract.Merge organic phase, with 4000 mL 5% sodium chloride solution washings, anhydrous Na
2sO
4dry.Rotary Evaporators boils off solvent, and the resistates obtained joins in 4L normal hexane and 6L toluene, vigorous stirring 1h, and stratification, discards organic layer, obtains pink liquid 201g, yield 89.1%.
4) preparation of 4-cyclopropyl-1-naphthalenylisothiocyanate
In the dry reaction still of 10L, add the toluene of 1-amino-4-cyclopropyl naphthalene (183g, 1.0mol), triethylene diamine (DABCO, 364g, 3.3 mol) and 6000mL drying, stirring at room temperature is dissolved, and then drips CS in what 30min
2(250g, 3.3 mol), add rear what room temperature and continue to stir 7h, separate out a large amount of solid, a small amount of toluene wash of solid.By above solid, in the toluene solution of suspension what 4L, stir at 0 DEG C ~ 5 DEG C, add toluene sulfonyl chloride, add rear stirring at room temperature 2h, then temperature rising reflux 1h makes to react completely, and is cooled to room temperature, cross and filter insolubles, filtrate is washed with 4000 mL 5% sodium chloride solutions, anhydrous Na
2sO
4dry.Rotary Evaporators boils off solvent, the residue by silicagel column chromatographic separation obtained, sherwood oil is eluting obtains colourless liquid 216g, yield 86.3%.
5) preparation of 3-amino-4-(4-cyclopropyl naphthalene-1-base)-1H-1,2,4-triazole-5 (4H)-thioketones
Cylite (120g is added in the dry reaction still of 5L, 0.7mol) with 380mL ethanol, ice-water bath cooling is lower stirs, and adds thiosemicarbazide (64g, 0.7mol), reaction mixture temperature rising reflux 0.5 h, the solution obtained is cooled to room temperature, adds 2000mL water, stirs, then 4-cyclopropyl-1-naphthalenylisothiocyanate (158 g, 0.7mol) and Na is added successively
2cO
3the aqueous solution 180mL of (38 g, 0.35mol), gained mixture at room temperature stirs and spends the night, and obtains a light yellow syrup after having reacted.Suction filtration, collect solid, a small amount of water washing, then ambient temperature in vacuum is dry, obtain a light yellow solid, reflux 0.5 h in 1800 mL ethanol, and after having reacted, reaction mixture is cooled to room temperature, obtain a yellow slurry, in the frozen water that impouring 5000mL stirs, continue to stir 20min, use CH
2cl
2(900mL × 3) extract.Merge organic phase, wash with the sodium chloride solution of 2500 mL 5%, anhydrous Na
2sO
4drying, filter, Rotary Evaporators boils off solvent, and the resistates obtained adds normal hexane 4000ml, stirring at room temperature 2h, filters, obtains light yellow solid 157 g, yield 77%, mp 260 DEG C (decomposition).HPLC content 97.9%.
6) preparation of 2-((5-amino-4-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulphur) methyl acetate
3-amino-4-(4-cyclopropyl naphthalene-1-base)-1H-1,2,4-triazole-5 (4H)-thioketones (142g, 0.5mol), solid K is added in the dry reaction still of 5L
2cO
3the DMF of (83g, 0.6mol) and 1800mL drying, gained mixture at room temperature stirs, then adds methyl bromoacetate (84g, 0.56mol), continues to stir 4h under room temperature.Reaction mixture is toppled in the frozen water of 5000mL stirring, continues to stir 30min, uses CH
2cl
2(1500mL × 3) extract.Merge organic phase, wash with the sodium chloride solution of 3500 mL 5%, anhydrous Na
2sO
4drying, Rotary Evaporators boils off solvent, and resistates butanone-methyl alcohol (1:1) recrystallization obtained, obtains white solid 164g, yield 91.8%, mp 164 ~ 166 DEG C.HPLC content 98.2%.
7) preparation of 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulphur) methyl acetate
To in the dry reaction still of 5L, by 2-((5-amino-4-(4-cyclopropyl naphthalene-1-base)-4H-1,2,4-triazole-3-base) sulphur) methyl acetate (142g, 0.4mol) be dissolved in 2500 mL bromofoms, stirred at ambient temperature, adds NaNO
2(276g, 0.4mol) and benzyl triethyl ammonium bromide (109g, 0.4mol), continue to stir, then add dichloro acetic acid (107g, 1.6mol), and gained mixture at room temperature continues to stir 4h.After having reacted, reaction mixture carefully pours in the frozen water of 6000mL stirring, continues to stir 30min, uses CH
2cl
2(1500 mL × 3) extract.Merge organic phase, use the Na of 2000 mL 5% successively
2s
2o
3the sodium chloride solution washing of solution and 2000 mL 5%, anhydrous Na
2sO
4drying, Rotary Evaporators boils off solvent, and the resistates acetic acid-acetone recrystallization obtained, obtains white crystalline solid 131 g, yield 79.2%.mp 41～43℃。HPLC content 97.6%.
8) preparation of 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl]-N-hydroxyl acetamide
To in the reactor of 10L, add ethanol 2000ml, oxammonium hydrochloride (24g, oxammonium hydrochloride aqueous solution 0.345mol) being mixed with 17% adds reactor, by mass concentration be 20% aqueous sodium hydroxide solution reaction pH value be adjusted to 12 ~ 12.5, add tetrabutylammonium chloride (4.17g, 0.015mol), under stirring at room temperature, instillation 2-((the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-1, 2, 4-triazole-3-base) sulphur) methyl acetate (125g, 1250ml ethanolic soln 0.3mol), instill the aqueous sodium hydroxide solution of 15% ~ 20% simultaneously, remain that the pH value of reaction system is stabilized in 12 ~ 12.5, dissolution of solid in question response liquid, 20 ~ 25 DEG C are stirred 2h, stopped reaction, by concentrated hydrochloric acid adjust ph to 4.5 ~ 5.0, leave standstill 2h, filter, obtain white powdery solids, ethyl alcohol recrystallization, vacuum 60 ~ 65 DEG C of dry 8h, obtain 105g, yield 84.1%.mp 102～104℃。HPLC content 99.2%.
1H—NMR（500MHz，CDCl
3/TMS，ppm）：
δ: 8.2(1H, bs, NH), 4.6(1H, bs, OH) and, 8.56(1H, d, J=9.7 Hz, Ar-H), 7.59 ~ 7.66(4H, m, Ar-H) and, 7.43(d, 1H, J=9.7 Hz, Ar-H), 7.21(1H, d, J=10.2Hz, Ar-H) and, 3.99(s, 2H, SCH
2), 2.52 ~ 2.65(m, 1H, cyclopropyl-CH), 1.06-1.20(m, 2H, cyclopropyl-CH
2), 0.87 ~ 0.94(2H, m, cyclopropyl-CH
2),
MS:m/z （M
+）418（100%）。
embodiment 2:the preparation of formula 1 compound sheet
Prescription:
Preparation technology:
1., pre-treatment: formula 1 compound, Zeparox, Microcrystalline Cellulose, cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and Magnesium Stearate were pulverized 100 mesh sieves respectively.
2., always mix: after formula 1 compound and Zeparox mixing, add Magnesium Stearate to increase mobility, mixing
Add other auxiliary materials again, mixing.
3., compressing tablet: direct compression, temperature 20 ~ 25 DEG C between compressing tablet, relative humidity controls 35 ~ 45%.
embodiment 3: biological activity determination
1, formula I is on the impact of mouse hyperuricemia
Laboratory animal: healthy Kunming mouse, body weight 15 ~ 20g, is provided by unming Medical College's Experimental Animal Center.Rearing conditions: room temperature is 25 scholar 2 DEG C, relative humidity 45 ~ 75%.
Grouping, modeling and administration: 40 Kunming mouses are divided into 4 groups at random, often organize 10, male and female half and half: Normal group, hyperuricemia model group, formula I group, lesinurad group.Normal group mouse peritoneal injection 0. 5% CMC-Na solution, all the other are group mouse peritoneal injection Oxonic Acid sylvite 500mg/kg respectively, Normal group and hyperuricemia model group mouse peritoneal injection equal-volume 0. 5% CMC-Na solution after 1 hour, all the other respectively organize mouse peritoneal injection test medicine.Within 2 hours, posterior orbit gets blood, and gathers urine sample.Enzymic colorimetric is adopted to measure serum uric acid and urine uric acid level.Result following (X scholar S, n=10):
Above-mentioned experiment shows, formula I can reduce serum uric acid concentration, has the effect of the suppression serum uric acid similar to Lesinurad group, and meanwhile, can significantly improve urine uric acid concentration again, its result for the treatment of is slightly remarkable.
2, formula I is on the impact experiment of rat urarthritis caused by Monosodium urate crystallization
Laboratory animal: healthy SD rat, body weight 250 ~ 300g, is provided by unming Medical College's Experimental Animal Center.Rearing conditions: room temperature 25 scholar 2 DEG C, relative humidity 45 ~ 75%.
Grouping, modeling and administration: SD rat 40, is divided into 4 groups at random, often organize 10, male and female half and half: Normal group, urarthritis model group, formula I group (6mg/kg), Lesinurad group (6mg/kg).The right Injection in knuckle articular cavity of rats in normal control group aseptic PBS 60 u 1, all the other 2% MSU50 u 1 that respectively group Rat Right Injection in knuckle articular cavity is aseptic, Normal group and model group rats abdominal injection equal-volume 0. 5% CMC-Na solution after 1 hour, all the other respectively organize rats by intraperitoneal injection test medicine.With the right knee joint girth of tape measuring after 24 hours, represent Articular swelling with the difference before itself and administration.Result following (X scholar S, n=10):
Above-mentioned experiment shows, with model group phase), prompting type I group Articular swelling reduces 56.5%, and (P<0. 001, prompting type I obviously can suppress rat gouty joint swelling caused by MSU.
Claims (8)
1. a new compound hydroxamic acid lesinurad, chemical name is 2-[the bromo-4-of 5-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazole-3-sulfanyl]-N-hydroxyl acetamide, and its structural formula is such as formula shown in I:
。
2. the preparation method of a kind of new compound hydroxamic acid lesinurad according to claim 1, is characterized in that:
Technological line is as follows:
。
3. the preparation method of new compound hydroxamic acid lesinurad according to claim 2, it is characterized in that: step 4 is synthesized 4-cyclopropyl-1-naphthalenylisothiocyanate and adopted dithiocarbonic anhydride-organic bases-SULPHURYL CHLORIDE decomposition method system, wherein said organic bases is diethylene diamine, 4-pyridyl pyridine or triethylamine, particularly preferably diethylene diamine; Described SULPHURYL CHLORIDE is methylsulfonyl chloride or toluene sulfonyl chloride, particularly preferably toluene sulfonyl chloride.
4. the preparation method of a kind of new compound hydroxamic acid lesinurad according to claim 2, is characterized in that: step 9 is synthesized new compound hydroxamic acid lesinurad and adopted phase transfer catalysis process.
5. the preparation method of a kind of new compound hydroxamic acid lesinurad according to claim 4, it is characterized in that: described catalyzer selects tetrabutylammonium chloride, benzyltriethylammoinium chloride, hexaoxacyclooctadecane-6, Macrogol 4000, preferred tetrabutylammonium chloride; In molar ratio, lesinurad methyl esters: oxammonium hydrochloride: mass concentration is 25% ~ 42% aqueous solution: tetrabutylammonium chloride is 1:1.1 ~ 1.2:2.5 ~ 3.5:0.02 ~ 0.1.
6. the preparation method of a kind of new compound hydroxamic acid lesinurad according to claim 4, is characterized in that: temperature of reaction is 15 ~ 30 DEG C.
7. the purposes of a kind of new compound hydroxamic acid lesinurad according to claim 1 in preparation treatment hyperuricemia and gout medicine.
8. the purposes of a kind of new compound hydroxamic acid lesinurad according to claim 1 in preparation treatment urarthritis medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106220577A (en) * | 2016-07-26 | 2016-12-14 | 苏州明锐医药科技有限公司 | The preparation method of Li Xinluode |
| CN107325060A (en) * | 2016-04-29 | 2017-11-07 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Lesinurad intermediates of crystal habit and preparation method thereof |
| CN109134391A (en) * | 2018-09-21 | 2019-01-04 | 山东大学 | A kind of acyl sulfonamides analog derivative and the preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120164222A1 (en) * | 2007-11-27 | 2012-06-28 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
-
2015
- 2015-04-14 CN CN201510173070.1A patent/CN104710374A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120164222A1 (en) * | 2007-11-27 | 2012-06-28 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
Non-Patent Citations (2)
| Title |
|---|
| 杜晓华等: ""非硫光气法合成一些难合成的芳基异硫氰酸酯"", 《农药》 * |
| 田禾等: ""lesinurad 的合成工艺研究"", 《现代药物与临床 DRUGS & CLINIC》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325060A (en) * | 2016-04-29 | 2017-11-07 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Lesinurad intermediates of crystal habit and preparation method thereof |
| CN106220577A (en) * | 2016-07-26 | 2016-12-14 | 苏州明锐医药科技有限公司 | The preparation method of Li Xinluode |
| CN109134391A (en) * | 2018-09-21 | 2019-01-04 | 山东大学 | A kind of acyl sulfonamides analog derivative and the preparation method and application thereof |
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Application publication date: 20150617 |