CN106032377A - Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout - Google Patents
Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout Download PDFInfo
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Abstract
The invention relates to the field of medicines for hyperuricemia and gout, and particularly relates to tetrazole type urate transporter 1 (URAT1) inhibitors, a preparing method, medical compositions containing the inhibitors, and uses of the inhibitors in treatment of hyperuricemia and gout. Each substitute is shown in the specification.
Description
Technical field
The present invention relates to the drug world of hyperuricemia and gout.In particular it relates to above-mentioned disease
Sick have a medicative class containing uric acid transporter body 1 (URAT1) inhibitor of tetrazole structure, its preparation side
Method, and contain their pharmaceutical composition and in purposes pharmaceutically.
Background technology
Gout is a kind of causing so that hyperuricemia and monosodium urate salt (MSU) are deposited on the positions such as joint bitterly
The chronic metabolic disease that pain is principal character, main cause is purine metabolic disturbance and/or uric acid discharge obstacle.
Whole world patient with gout has tens million of at present.
Current hyperuricemia and gout treatment drug main to include: i) for gout acute attack swollen joint
The antiinflammation pain-stopping pharmaceutical that the symptoms such as swollen, pain control, such as colchicine and nonsteroidal anti-inflammatory drug (NSAID) etc.；
Ii) for suppressing the medicine of uricopoiesis, such as xanthine oxidases such as allopurinol, oxipurinol and Febuxostats
(XO) inhibitor；Iii) for the medicine of urate excretion, such as probenecid and benzbromarone etc.；Iv) for acute
The uricolysis medicine of blood uric acid is reduced rapidly, such as uricase (uricase) and Pegylation during gout outbreak
Uricase (pegloticase).But, these medicines are respectively provided with the more serious side effect of ratio, as colchicine has
There are common untoward reaction such as diarrhoea, vomiting, abdominal cramp, and are the first indication of its toxicity, treatment
Effective dose causes the comparable doses of gastrointestinal symptom with it；Probenecid can cause renal colic and renal function injury；
Benzbromarone has the danger causing explosive hepatitis；Allopurinol has liver and bone marrow toxicity and allergy etc. no
Good reaction；Uricase preparation is drug administration by injection, and the compliance of patient is not so good as oral formulations, is only adapted to acute pain
Blood uric acid is reduced during wind outbreak, should not be as long-term treatment.
Uric acid transporter body 1 (urate transporter 1, URAT1) is positioned at the brush of the epithelial cell of renal proximal tubules
On shape edge, it is the important uric acid transporter body being positioned at kidney of discovered in recent years, is responsible for the heavily absorption of uric acid in kidney
(Enomoto,A.；Kimura,H.；et al.Nature,2002,vol 417,447-452).It will be apparent that suppression
URAT1 will suppress heavily the absorbing of uric acid in kidney, increase the excretion of uric acid in urine, and then reduces
Blood uric acid and the purpose of control gout outbreak.Preclinical study and the clinical research of Lesinurad etc. have been proven that
URAT1 inhibitor curative effect (Fleischmann, R. in terms for the treatment of hyperuricemia and gout；Kerr,B.；et
al.Rheumatology,2014,vol 53,2167-2174)。
Lesinurad (RDEA 594) is that a kind of URAT1 that can suppress developed by Ardea company discharges blood
The oral drugs of uric acid in liquid, are developed (following institute by antiviral drugs RDEA806 of Valeant the earliest
Show).Lesinurad already at III phase clinical investigation phase (US2013345271 and WO2014008295),
Its proprietary rights already belongs to Astra Zeneca.
The invention discloses the class URAT1 inhibitor containing tetrazole structure, these compounds can be used for preparing
Hyperuricemia and the medicine of gout.
Summary of the invention
It is an object of the present invention to provide a kind of URAT1 inhibitor with general formula I and pharmaceutically
Acceptable salt.
It is a further object to provide preparation there is the compound of general formula I and pharmaceutically can connect
The method of the salt being subject to.
It is also another object of the present invention to provide the compound containing general formula I and pharmaceutically acceptable thereof
Salt is as effective ingredient, and one or more pharmaceutically acceptable carriers, excipient or diluent is medicinal
Compositions, and the application in terms for the treatment of gout and hyperuricemia.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of general formula I and has a following structural formula:
Wherein, R is selected from H, C1-C10Alkyl, C3-C10Cycloalkyl, F, Cl, Br, I, CN, NO2,
SR2And OR2, wherein R2Selected from C1-C10Alkyl and C3-C10Cycloalkyl.
Preferably below general formula I,
Wherein, R is selected from H, C1-C4Alkyl, C3-C6Cycloalkyl, F, Cl, CN, NO2And OR2,
Wherein R2Selected from C1-C4Alkyl and C3-C6Cycloalkyl.
The compound with general formula I more preferably is as follows,
It should be noted that as compound I of the present invention, the unsubstituted tetrazole of nitrogen-atoms
Derivant, there is the tautomeric equilibrium of the following two kinds form, can write in practice and appoint in its tetrazole part
What is a kind of.
Compound of Formula I of the present invention can be synthesized by following route:
Compound II (US2013345271) and compound III (Russian Journal of Organic Chemistry,
2006,42 (7), 1049-1055) prepare according to literature method.
There is substitution reaction in compound II and compound III, generates compound IV in the presence of a base；Compound IV
Bromination obtains target product I；Compound I can become salt to obtain the pharmaceutically acceptable salt I-S of correspondence；Its
Middle R's is defined as described above.
Described alkali can be organic base or inorganic base, organic base such as triethylamine, diisopropyl ethyl amine, inorganic base
Such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide.
Described bromide reagent can be: NaNO2/ acid/bromofom, NaNO2/CuBr2, wherein/represent between reagent
Relation associated with being, described acid can be various organic acid, such as acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoro
Acetic acid.In some cases, the compound I that directly synthesized by IV purifies relatively difficult, now can be by
Following strategy: crude Compound I reacts with trityl chloride (TrCl), and its N-2 is partially alkylated or alkylated, and is produced
Thing V, this compound is easily purified by column chromatography and recrystallization, and the V after purification uses acid treatment, sloughs Tr
After, retrieve product I.
The pharmaceutically acceptable salt of compound of formula I of the present invention includes, but are not limited to and various inorganic bases,
Such as, NaOH, KOH, Mg (OH)2、Ca(OH)2、Sr(OH)2、Al(OH)3Deng, or inorganic carbonate,
Such as Na2CO3、K2CO3、MgCO3、CaCO3、SrCO3Deng, or organic base, such as aminoacid etc.,
The pharmaceutically acceptable salt generated.
Compound of formula I of the present invention, can with one or more pharmaceutically acceptable carriers, excipient or
Diluent makes pharmaceutical composition jointly.This pharmaceutical composition can make solid orally ingestible, liquid port system of mourning
The dosage form such as agent, injection.Described solid and liquid oral medicine include: dispersible tablet, sugar-coat agent, granule,
Dry powder doses, capsule and solution.Described injection includes: little pin, infusion solutions, freeze-dried powder etc..
The compositions of the present invention, in described pharmacy or bromatology, acceptable adjuvant is selected from: filler, disintegrating agent,
Lubricant, fluidizer, effervescent, correctives, preservative, coating material or other excipient.
The compositions of the present invention, acceptable adjuvant in described pharmacy or bromatology.Filler is that filler includes
Lactose, sucrose, dextrin, starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate,
Calcium carbonate, the compositions of one or more of microcrystalline Cellulose；Described binding agent includes sucrose, starch, gathers
Dimension ketone, sodium carboxymethyl cellulose, hypromellose, hydroxypropylcellulose, methylcellulose, Polyethylene Glycol,
Medicinal alcohol, the compositions of one or more of water；Described disintegrating agent includes starch, crosslinking polyvidone, friendship
Connection sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carmethose, the one of gas-producing disintegrant or
Several compositionss.
Compound of Formula I of the present invention has URAT1 inhibitory action, can be used for preparing as effective ingredient
Gout and the medicine of hyperuricemia.The activity of compound of Formula I of the present invention is to pass through vitro inhibition
Have expressed the cell pair of URAT114The absorption experiment of the uric acid of C-labelling is verified.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The agent that such as every day takes
Amount, about in the range of 1mg-1000mg/ people, is divided into once or is administered for several times.Actual take formula I of the present invention
The dosage of compound can be determined according to relevant situation by doctor.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only
For illustrating, and it is not intended to limit the present invention.Those skilled in the art are made according to the teachings of the present invention
Various changes all should be within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I-1
The synthesis of step 1. compound IV-1
Compound II-1 (2.82g, 10mmol), compound III (1.78g, 15mmol), KI (1.66g, 10
And K mmol)2CO3(4.15g, 30mmol) joins in the dry round-bottomed flask of a 250mL, adds
DMF(100mL).Gained reactant mixture stirs at 80 DEG C in nitrogen atmosphere, until TLC shows instead
(general about 6h) should be completed.
After reactant mixture cooling, it is poured in frozen water (1000mL), stirring, gained mixture pH > 7,
First use CH2Cl2(200mL × 3) extract, and discard organic facies, and aqueous phase regulates pH=3 with concentrated hydrochloric acid again, again
Use CH2Cl2(300mL × 5) extract.Merge extraction organic facies, use 5% brine It, anhydrous Na2SO4
It is dried.Dried organic facies boils off solvent on a rotary evaporator, the residue obtained through column chromatography purification,
Obtain product IV-1, pale yellow foam solid, 3.02g, productivity 83%.1H NMR(DMSO-d6,400
MHz), δ 8.53 (d, 1H, J=8.4Hz), 7.67-7.71 (m, 1H), 7.56-7.60 (m, 1H), 7.41 (d, 1H,
J=7.6Hz), 7.36 (d, 1H, J=7.6Hz), 7.17 (d, 1H, J=8.4Hz), 6.05 (bs, 2H), 4.31 (s,
2H),2.51-2.53(m,1H),1.12-1.15(m,2H),0.79-0.86(m,2H).
The synthesis of the crude product of step 2. compound I-1
Compound IV-1 (2.19g, 6mmol) is dissolved in bromofom (20mL), the lower stirring of ice-water bath cooling, adds
NaNO2(8.28g, 120mmol) and benzyl triethyl ammonium bromide (1.63g, 6mmol), the most slowly drip two
Monoxone (3.09g, 24mmol), after dropping, compound of reaction at room temperature continues stirring, until TLC
Display reaction completes (general about 5h).
Reactant mixture pours in water (200mL), stirring, regulates pH=3 with hydrochloric acid, uses CH2Cl2(100
ML × 5) extraction.Merge extraction organic facies, with containing 1% Na2S2O35% brine It, anhydrous Na2SO4
It is dried.Dried organic facies boils off solvent on a rotary evaporator, and the residue obtained is through column chromatography purification
Remove the obvious incoherent impurity of polarity, obtain the crude product of product I-1, pale yellow foam solid, 1.62g, produce
Rate 63% (based on crude product).
The synthesis of step 3. compound V-1
The crude product (1.28g counts according to 3mmol) of compound I-1 is dissolved in dry CH2Cl2(15mL) in, ice
The lower stirring of water-bath cooling, adds diisopropyl ethyl amine (DIPEA, 1.16g, 9mmol), is then dividedly in some parts
Trityl chloride (TrCl, 1.39g, 5mmol).Gained reactant mixture refluxes overnight under nitrogen protection.
After reactant mixture cooling, it is poured in frozen water (100mL), stirring, CH2Cl2(100mL × 3) extract
Take, merge extraction organic facies, successively with 1% dilute hydrochloric acid (100mL) and with 5% saline solution (100mL) washing,
Anhydrous Na2SO4It is dried.Dried organic facies boils off solvent on a rotary evaporator, the residue warp obtained
Cross column chromatography purification, obtain product V-1, obtain after crystallization from ethyl acetate/normal hexane (volume ratio=1/10)
One white solid, is high-purity V-1,1.63g, productivity 81%.Fusing point 180-182 DEG C；1H NMR
(DMSO-d6, 400MHz), δ 8.54 (d, 1H, J=8.8Hz), 7.64-7.68 (m, 1H), 7.29-7.43 (m,
12H), 6.95-6.99 (m, 6H), 6.90 (d, 1H, J=8.4Hz), 4.54 (d, 1H, J=15.2Hz), 4.40 (d,
1H, J=14.8Hz), 2.51-2.54 (m, 1H), 1.11-1.16 (m, 2H), 0.83-0.85 (m, 2H).
The synthesis of step 4. compound I-1
Compound V-1 (1.34g, 2mmol) is dissolved in the aqueous formic acid (26mL) of 90%, then gained reaction
Mixture stirs at 80 DEG C, until TLC checks that reaction completes (general about 5 hours).
After reactant mixture cooling, boil off overwhelming majority solvent on a rotary evaporator, be then poured into 100mL
In frozen water, stirring, regulate pH=3, CH with concentrated hydrochloric acid2Cl2(100mL × 3) extract, and merge extraction organic
Phase, washs with 5% saline solution (100mL), anhydrous Na2SO4It is dried.Dried organic facies is at rotary evaporation
Boiling off solvent on instrument, the residue obtained, through short column column chromatography purification, obtains product I-1, white foam
Solid, 0.86g, productivity 91%.1H NMR(DMSO-d6, 400MHz), δ 8.57 (d, 1H, J=8.4Hz),
7.73 (t, 1H, J=7.4Hz), 7.58-7.63 (m, 2H), 7.41 (d, 1H, J=7.6Hz), 7.08 (d, 1H, J=
8.4Hz), 4.63 (d, 1H, J=15.6Hz), 4.59 (d, 1H, J=15.2Hz), 2.52-2.58 (m, 1H),
1.13-1.16(m,2H),0.83-0.86(m,2H).
The synthesis of embodiment 2-16 compound I-2 to I-16
The method of reference example 1, has synthesized and following has had compounds of formula I.
Embodiment 17 is synthesized sodium salt I-S-1 by compound I-1
Compound I-1 (0.428g, 1mmol) is dissolved in methanol (5mL), under room temperature stir, be slowly added into by
The solution that NaOH (0.400g, 1mmol) and water (1mL) are prepared, after adding, reactant mixture at room temperature continues
Continuous stirring 10 minutes.
Reactant mixture is evaporated on a rotary evaporator, after residue methanol (20mL × 2) dissolving obtained again
Be evaporated so that the water removing in residue, the residue obtained further in vacuum oil pump the water-bath of 35 DEG C
In be dried 12 hours, obtain the sodium salt I-S-1 of I-1, white solid, 0.441g, productivity 98%.1H NMR
(DMSO-d6, 400MHz), δ 8.55 (d, 1H, J=8.4Hz), 7.71 (t, 1H, J=7.4Hz), 7.62 (t, 1H,
J=7.6Hz), 7.56 (d, 1H, J=7.6Hz), 7.40 (d, 1H, J=7.6Hz), 7.12 (d, 1H, J=8.4
Hz), 4.47 (d, 1H, J=14.0Hz), 4.43 (d, 1H, J=14.4Hz), 2.51-2.56 (m, 1H),
1.11-1.15(m,2H),0.83-0.87(m,2H).
Embodiment 18-32 is synthesized its sodium salt I-2-S to I-24-S by compound I-2 to I-24
With reference to the method for embodiment 17, compound I-2 to I-16 can be converted into the sodium salt I-S-2 of its correspondence
To I-S-16.
Embodiment 33
| Component | Consumption/grain |
| Embodiment 1 sample | 100mg |
| Microcrystalline Cellulose | 30mg |
| Pregelatinized Starch | 20mg |
| Polyvinylpyrrolidone | 3mg |
| Magnesium stearate | 2mg |
| Pulvis Talci | 1mg |
Active component, pregelatinized Starch and microcrystalline Cellulose are sieved, is sufficiently mixed, add polyvinylpyrrolidine
Ketone solution, mixing, soft material processed, sieve, wet granular processed, it is dried in 50-60 DEG C, by magnesium stearate and Talcum
Powder sieves in advance, is then added in above-mentioned granule, encapsulated, to obtain final product.
Embodiment 34
| Component | Consumption/sheet |
| Embodiment 2 sample | 300mg |
| Microcrystalline Cellulose | 80mg |
| Pregelatinized Starch | 70mg |
| Polyvinylpyrrolidone | 6mg |
| Sodium carboxymethyl starch | 5mg |
| Magnesium stearate | 2mg |
| Pulvis Talci | 2mg |
Active component, pregelatinized Starch and microcrystalline Cellulose are sieved, is sufficiently mixed, add polyvinylpyrrolidine
Ketone solution, mixing, soft material processed, sieve, wet granular processed, it is dried in 50-60 DEG C, by Sodium carboxymethyl starch,
Magnesium stearate and Pulvis Talci sieve in advance, are then added to tabletting in above-mentioned granule.
Embodiment 35
| Component | Consumption/50mL |
| Embodiment 3 sample | 10mg |
| Citric acid | 100mg |
| NaOH | (adjust pH 4.0-5.0) in right amount |
| Distilled water | 50mL |
In distilled water, be initially charged distilled water and citric acid, stirring and dissolving and after, add sample, slight fever
Making dissolving, tune pH value is 4.0-5.0, adds 0.2g activated carbon, stirs 20 minutes under room temperature, filters, filter
Liquid, middle control measures solution concentration, by every ampulla 5mL subpackage, high temperature sterilize 30 minutes, obtains injection.
Embodiment 36
| Granule component | / 100 bags |
| Embodiment 4 sample | 10.0g |
| Lactose | 55.0g |
| Mannitol | 14.0g |
| Aspartame | 0.05g |
| Essence | 0.05g |
| 2% hypromellose (pure water preparation) | QS |
Preparation technology: principal agent is crossed respectively with adjuvant 100 mesh sieves, is sufficiently mixed, then weighs recipe quantity adjuvant
It is sufficiently mixed with principal agent.Adding binding agent soft material, 14 mesh sieves are pelletized, and 55 DEG C are dried, 12 mesh sieve granulate,
Measure bag heavily to pack.
Embodiment 37
| Component | Consumption |
| Embodiment 5 sample | 2.0g |
| Poloxamer | 1.0g |
| Sodium hydroxide | 0.2g |
| Citric acid | QS |
| Mannitol | 26.0g |
| Lactose | 23.0g |
| Water for injection | 100mL |
Preparation technology: take water for injection 80mL, add principal agent, mannitol, lactose, poloxamer stirring make molten
Xie Hou, the citron acid for adjusting pH adding 1mol/L adds water to 100mL to 7.0-9.0, benefit.Add 0.5g to live
Property charcoal, stir 20 minutes at 30 DEG C, de-charcoal, use filtering with microporous membrane degerming, filtrate presses every 1mL
Carrying out subpackage, pre-freeze is after 2 hours, freezing lower drying under reduced pressure 12 hours, to sample temperature to room temperature after, then
It is dried 5 hours, prepares white loose block, seal and get final product.
Embodiment 38 Compound ira vitro suppression URAT1 analyzes
After trypsinization, express cell (HEK293) and the mock cell of stable expression URAT1 gene are all connect
Planting and be coated 24 hole culture plates in lysine, cell-seeding-density is 1 × 105Individual/hole, at 37 DEG C, 5%CO2、
Cultivate 2 days in the incubator of saturated humidity.Remove culture fluid in culture plate, cell DPBS will be cultivated and clean two
Secondary, and bathe 10min 37 DEG C of middle temperature of DPBS buffer, then contain radiolabeled probe with 500 μ L
Substrate ([8-14C] uric acid) and 10 μMs of testing compounds (or blank) solution replacement DPBS, [8-14C] uric acid
Concentration is 5 μMs.After 2min, terminate reaction with ice bath DPBS buffer, and clean 3 times, the most each Kong Tian
Adding 500 μ L 0.1mol/L NaOH cell lysis, extraction lysate, in scintillation vial, adds the scintillation solution of 3mL
(Aquasol-2), and with Tri-Carb 2910TR liquid scintillation instrument (PerkinElmer, Waltham, USA) measure in sample
Radioactive intensity.
Use the data of said determination according to the following equation calculating testing compound suppression ratio to URAT1:
Suppression ratio=(control-test compound)/(control-mock) × 100%
Wherein: control=is without radioactive intensity corresponding to the hole of testing compound
The radioactive intensity that the hole of test compound=testing compound is corresponding
The radioactive intensity that the hole of the blanc cell of mock=untransfected URAT1 is corresponding
Result collects and see table 1.
Table 1 vitro inhibition URAT1 analyzes result of the test
| Testing compound | Suppression ratio (%) | Testing compound | Suppression ratio (%) |
| Lesinurad | 59 | I-7 | 70 |
| I-S-1 | 70 | I-S-8 | 68 |
| I-1 | 70 | I-S-9 | 73 |
| I-S-2 | 71 | I-S-10 | 70 |
| I-S-3 | 69 | I-S-11 | 68 |
| I-S-4 | 72 | I-S-12 | 67 |
| I-S-5 | 66 | I-S-13 | 75 |
| I-S-6 | 73 | I-S-14 | 66 |
| I-6 | 72 | I-S-15 | 69 |
| I-S-7 | 70 | I-S-16 | 72 |
From upper table result it can be seen that the compound of the present invention has the strongest inhibitory action to URAT1, and
Generally it is better than the URAT1 inhibitor containing acetic acid structure with lesinurad as representative, can be as preparation treatment
Gout and the medicine of hyperuricemia.And it should be noted that the compound of the present invention itself is corresponding
Sodium salt activity is basically identical.
Claims (9)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R is selected from H, C1-C10Alkyl, C3-C10Cycloalkyl, F, Cl, Br, I, CN, NO2,
SR2Or OR2, wherein R2Selected from C1-C10Alkyl or C3-C10Cycloalkyl.
There is compound and the pharmaceutically acceptable salt thereof of general formula I the most as claimed in claim 1,
Wherein, R is selected from H, C1-C4Alkyl, C3-C6Cycloalkyl, F, Cl, CN, NO2Or OR2,
Wherein R2Selected from C1-C4Alkyl or C3-C6Cycloalkyl.
There is compound and the pharmaceutically acceptable salt thereof of general formula I the most as claimed in claim 2, be selected from
Following compounds,
4. the synthesis method surely stating the compound with general formula I as arbitrary in claim 1-3:
There is substitution reaction in compound II and compound III, generates compound IV in the presence of a base；Compound IV
Bromination obtains target product I；Compound I can become salt to obtain the pharmaceutically acceptable salt I-S of correspondence；Its
The definition of middle R is as described in any one of claim 1-3.
5. a method for the purification compound with general formula I as described in any one of claim 1-3, it is special
Levy and be:
Crude Compound I reacts with trityl chloride, and its N-2 is partially alkylated or alkylated, and obtains product V, this compound
Purify through column chromatography and recrystallization；V after purification uses acid treatment, after sloughing trityl-protecting group,
To the product I that purity is higher.
6. the compound with general formula I described in any one of claim 1-3 is at preparation treatment gout and metabolic arthritis
Application in terms of mass formed by blood stasis medicine.
7. a pharmaceutical composition, containing the compound with general formula I as described in any one of claim 1-3,
And suitable carrier or excipient.
8. pharmaceutical composition as claimed in claim 7, wherein, described compositions is solid orally ingestible, liquid
Body oral formulations or injection.
9. solid as claimed in claim 8 and liquid oral medicine include: dispersible tablet, enteric coatel tablets, chewable tablet,
Oral cavity disintegration tablet, capsule, granule, oral solution, described injection preparation includes injection liquid drugs injection, injection
Freeze-dried powder, infusion solutions, primary infusion.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108524518A (en) * | 2018-04-28 | 2018-09-14 | 通化师范学院 | A kind of antigout effect of tetrazole compound |
| WO2019101058A1 (en) * | 2017-11-23 | 2019-05-31 | 基石药业（苏州）有限公司 | Crystal form of urat1 inhibitor, and preparation method therefor |
| CN111592558A (en) * | 2019-02-20 | 2020-08-28 | 北京桦冠医药科技有限公司 | Heterocyclic compound having uric acid reabsorption inhibiting effect |
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| JP2021504353A (en) * | 2017-11-23 | 2021-02-15 | メッドシャイン ディスカバリー インコーポレイテッド | Crystal form of URAT1 inhibitor and its production method |
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