CN104341363B - A kind of nitro substituted triazole sulphonyl malonic acid compounds, Preparation Method And The Use - Google Patents
A kind of nitro substituted triazole sulphonyl malonic acid compounds, Preparation Method And The Use Download PDFInfo
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- CN104341363B CN104341363B CN201410583838.8A CN201410583838A CN104341363B CN 104341363 B CN104341363 B CN 104341363B CN 201410583838 A CN201410583838 A CN 201410583838A CN 104341363 B CN104341363 B CN 104341363B
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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
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Abstract
The present invention relates to the drug world relevant to hyperuricemia and gout.Specifically, the present invention relates to uric acid transporter body 1 inhibitor of a kind of nitro substituted triazole sulphonyl malonic acid structure, its preparation method and pharmaceutical composition and its application in preparing diabetes medicament containing it.
Description
Technical field
The present invention relates to treat the drug world that hyperuricemia is relevant with gout.Specifically, the present invention
Relate to a kind of nitro substituted triazole sulphonyl malonic acid structure medicative to hyperuricemia and gout
Uric acid transporter body 1 (urate transporter 1, URAT1) inhibitor, preparation method, containing its medicine group
Compound and in purposes pharmaceutically.
Background technology
Gout is a kind of chronic metabolic disease, is deposited on hyperuricemia and monosodium urate salt (MSU)
The positions such as joint and the pain that causes is principal character, main cause is purine metabolic disturbance and/or urate excretion
Obstacle.According to estimates, whole world patient with gout has more than 2,000 ten thousand at present.The medicine being currently used for treating gout includes
For lenitive anti-inflammatory drug (such as colchicine etc.), suppression uricopoiesis medicine (with allopurinol and Fei Busuo
The smooth xanthine oxidase inhibitor for representative), thick urate excretion medicine is (with probenecid, sulphinpyrazone, benzene bromine
Ma Long and the urate excretion medicine that losartan is representative) and uricase (with pegloticase as representative).These medicines
There is the toxic and side effects of different degree, cause the danger of explosive hepatitis as benzbromarone has, allopurinol has liver
Dirty and the untoward reaction such as bone marrow toxicity and allergy, etc..
Lesinurad (RDEA 594) is a kind of can be suppressed uric acid in kidney by what Ardea company developed
Transporter (urate transporter 1, URAT1) and discharged the oral medicine of uric acid in blood by the approach of urine
Thing, is currently in III phase clinical stage.The antiviral drugs that Lesinurad is researched and developed by Valeant company the earliest
RDEA806 develops.The proprietary rights of Lesinurad is purchased due to Ardea company at present and is belonged to now
Astra Zeneca。
The invention discloses a kind of URAT1 containing nitro substituted triazole sulphonyl malonic acid structure suppression
Agent, these compounds can be used for preparation treatment hyperuricemia and the medicine of gout.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, there is the compound of Formulas I.
It is a further object to provide the method that preparation has the compound of Formulas I.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of Formulas I and has a following structural formula:
Compound of formula I of the present invention has the inhibitory action of URAT1, can be used for making as effective ingredient
Standby hyperuricemia and the medicine of gout.The activity of compound of formula I of the present invention is to be combined by receptor
Verify.
The compound of formula I of the present invention is effective in comparatively wide dosage range.Such as every day takes
Dosage, about in the range of 1mg-500mg/ people, is divided into once or is administered for several times.Actual take formula Iization
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
It is only for explanation, and is not intended to limit the present invention.Those skilled in the art are done according to the teachings of the present invention
The various changes gone out all should be within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I
A. the synthesis of compound IV
5.74g (20mmol) compound II and 4.22g (20mmol) compound III is dissolved in 100mL to be done
In dry DMF, stir under room temperature, add 8.29g (60mmol) solid K2CO3, then reactant mixture
It is stirred at room temperature, until TLC follows the tracks of finds that reaction completes (within general 12h).Reactant mixture pours into
In 400mL frozen water, stirring, use the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses 100
The saline washing of mL 5%, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is steamed on a rotary evaporator
Dry, the residue obtained uses column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=440
([M+Na]+)。
B. the synthesis of compound V
5.00g (12mmol) compound IV is dissolved in 30mL bromofom, stirs under room temperature, adds 3.45g
(50mmol)NaNO2With 3.00g benzyl triethyl ammonium bromide, then add 6.45g (50mmol) two chloroethene
Acid.Gained mixture is stirred at room temperature, until TLC follows the tracks of finds that reaction completes (within general 12h).Instead
Mixture is answered to pour in 300mL frozen water, stirring, use the CH of 100mL × 32Cl2Extraction, merges
Extraction phase, uses the Na of 100mL 2% successively2S2O3The saline washing of solution and 100mL 5%, anhydrous sulfur
Acid sodium is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses post layer
Analysis purification, obtains compound V, white solid, ESI-MS, m/z=504 ([M+Na]+)。
C. the synthesis of compound VI
3.85g (8mmol) compound V is dissolved in 30mL methanol, stirs under room temperature, adds 3mL 10%
LiOH solution, under gained mixture room temperature stir, until TLC follow the tracks of find reaction complete (general 3h
Within).Reactant mixture pours in 200mL frozen water, stirring, use concentrated hydrochloric acid regulation pH=2-3, and 100
The CH of mL × 32Cl2Extraction, merges extraction phase, uses the saline washing of 100mL 5%, anhydrous sodium sulfate
It is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography pure
Change, obtain compound VI, white solid, ESI-MS, m/z=453,451 ([M-H]-).
D.The synthesis of compound I
2.72g g (6mmol) compound VI is dissolved in 20mL CH2Cl2In, stirring, add 2.40g (14
Mmol) metachloroperbenzoic acid (mCPBA), stirs 5h hour under room temperature.Reactant mixture pours into 200mL
In frozen water, stirring, the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses 100mL 2% successively
Na2S2O3The saturated NaHCO of solution, 100mL3Washing with the saline of 100mL 5%, anhydrous sodium sulfate is dried.
Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification,
To compound I-1, white-yellowish solid, ESI-MS, m/z=485,483 ([M-H]-).。
The preparation of embodiment 2 control compounds I-2
For fully contrasting the beneficial effect of the compounds of this invention, the present invention is prepared for being all and applicants have discovered that
Undocumented novel compounds as a comparison, concrete structure is as follows:
Its preparation method is as follows:
A. the synthesis of compound IV-2
4.84g (20mmol) compound II-2 and 4.22g (20mmol) compound III-2 is dissolved in 100mL
In the DMF being dried, stir under room temperature, add 8.29g (60mmol) solid K2CO3, then react mixing
Thing is stirred at room temperature, until TLC follows the tracks of finds that reaction completes (within general 12h).Reactant mixture is toppled over
Enter in 400mL frozen water, stirring, use the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses
The saline washing of 100mL 5%, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is at Rotary Evaporators
On be evaporated, the residue that obtains uses column chromatography purification, obtains compound IV-2, white solid, ESI-MS,
M/z=395 ([M+Na]+)。
B. the synthesis of compound V-2
4.46g (12mmol) compound IV-2 is dissolved in 30mL bromofom, stirs under room temperature, adds 3.45
g(50mmol)NaNO2With 3.00g benzyl triethyl ammonium bromide, then add 6.45g (50mmol) dichloro
Acetic acid.Gained mixture is stirred at room temperature, until TLC follows the tracks of finds that reaction completes (within general 12h).
Reactant mixture pours in 300mL frozen water, stirring, uses the CH of 100mL × 32Cl2Extraction, closes
And extraction phase, use the Na of 100mL 2% successively2S2O3The saline washing of solution and 100mL 5%, anhydrous
Sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses post
Chromatography purification, obtains compound V-2, white solid, ESI-MS, m/z=459 ([M+Na]+)。
C. the synthesis of compound VI-2
3.48g during (8mmol) compound V-2 is dissolved in 30mL methanol, stir under room temperature, add 3mL
The LiOH solution of 10%, stirs under gained mixture room temperature, until TLC follows the tracks of finds that reaction completes (typically
Within 3h).Reactant mixture pours in 200mL frozen water, stirring, uses concentrated hydrochloric acid regulation pH=2-3,
The CH of 100mL × 32Cl2Extraction, merges extraction phase, uses the saline washing of 100mL 5%, anhydrous sulfur
Acid sodium is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses post layer
Analysis purification, obtains compound VI-2, white solid, ESI-MS, m/z=406,408 ([M-H]-)。
D.CompoundI-2Synthesis
2.44g (6mmol) compound VI is dissolved in 10mL CH2Cl2, stirring, adds 1.24g (7.2
Mmol) metachloroperbenzoic acid (mCPBA), stirs 5h hour under room temperature.Reactant mixture pours into 200mL
In frozen water, stirring, the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses 100mL 2% successively
Na2S2O3The saturated NaHCO of solution, 100mL3Washing with the saline of 100mL 5%, anhydrous sodium sulfate is dried.
Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification,
To compound I-2, white solid, ESI-MS, m/z=424,422 ([M-H]-)。
Embodiment 3
The IC that URAT1 is suppressed by compound of the present invention and related compound50It is worth and remembers according to document
The similar method carried measures (embodiment 12 in US2014/0005136).
Build the cell strain stably expressing humanization URAT1 transporter: by humanization URAT1 gene
(SLC22A112) plasmid of eukaryotic expression it is subcloned into from plasmid pCMV6-XL-5 (Origene)
On pCMV6/neo (Origene).Gene sequencing confirms humanization URAT1 and the information of record in gene bank
Unanimously (NM_144585.2).HEK293 human embryonic kidney cell (ATCC#CRL-1573) is in EMEM tissue training
In nutrient solution 5% CO2Cultivate with in the air atmosphere of 95%.Use L2000 type transfection agents (Invitrogene)
PCMV6/Neo/URAT1 is transfected on HEK293 cell.After 24 hours, transfected cell is divided
In the tissue culture dishes of a diameter of 10cm, continued growth one day, then culture medium is replaced by containing 0.5
The fresh culture medium of mg/mL G418 (Gibco).After 8 days, select and collect drug resistance bacterium colony, and using it
It is right to test14The transport activity of the uric acid of C-labelling.By HEK293/URAT1 cell with the density in 75,000/ hole
Plant on 96 orifice plates that poly-D-Lys covers.
These cells grow overnight at 37 DEG C in incubator, are then cooled under room temperature, training therein
Nutrient solution uses the cleanout fluid in 250 μ L/ holes to washed once (125mM sodium gluconate, the 10m of pH=7.3
MHEPES).Testing compound or blank are added to containing 40 μMs14C-labelling uric acid
(54mCi/mmol), in buffer, described buffer contains 125mM sodium gluconate, 4.8mM Fructus Vitis viniferae
Saccharic acid potassium, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconate, 5.6mM Portugal
Grape sugar, 25mM HEPES, final pH=7.3.96 orifice plates at room temperature cultivate 10 minutes, the most successively
Three times are respectively cleaned with the above-mentioned cleanout fluid in 50 μ L/ holes and 250 μ L/ holes.96 orifice plates add Microscint 20
Type liquid dodges agent, and plank is overnight incubation at 45 DEG C, then reading on TopCount Plate Reader, and
Calculate IC accordingly50。
Shown in the following list of result:
The part of compounds of the present invention IC to URAT150Value
| Compound | IC50(hURAT1, nM) |
| Lesinurad | 22.4 |
| The compounds of this invention I | 9.4 |
| Control compounds I-2 | 30.7 |
Above-mentioned IC50Measurement result show, the compounds of this invention is strong URAT1 inhibitor, permissible
It is used for preparing treatment hyperuricemia and the medicine of gout.
Claims (3)
1. there is the compound of Formulas I structure,
2. the method for the compound of Formulas I described in synthesis claim 1:
Compound II reacts in the presence of a base with alpha-brominated dimethyl malenate, obtains compound IV；Compound
IV reacts with sodium nitrite and dichloroacetic acid in bromofom and obtains compound V；Compound V is in the basic conditions
Hydrolysis obtains compound VI；Compound VI and 2 equivalents and above oxidizing obtain compound I.
3. the purposes in terms of preparation treatment hyperuricemia and gout medicine of the compound described in claim 1.
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| CN201410583838.8A CN104341363B (en) | 2014-10-27 | 2014-10-27 | A kind of nitro substituted triazole sulphonyl malonic acid compounds, Preparation Method And The Use |
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| CN201410583838.8A CN104341363B (en) | 2014-10-27 | 2014-10-27 | A kind of nitro substituted triazole sulphonyl malonic acid compounds, Preparation Method And The Use |
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| CN104341363B true CN104341363B (en) | 2016-08-17 |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RS52632B (en) * | 2004-08-25 | 2013-06-28 | Ardea Biosciences Inc. | S-triazolyl alpha-mercaptoacetanilides as inhibitors of hiv reverse transcriptase |
| EA201270666A1 (en) * | 2007-11-27 | 2012-12-28 | Ардеа Биосайнсиз Инк. | COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR REDUCING URIC ACID LEVEL |
| EP2328879A4 (en) * | 2008-09-04 | 2012-05-09 | Ardea Biosciences Inc | Compounds, compositions and methods of using same for modulating uric acid levels |
| JP2012527475A (en) * | 2009-05-20 | 2012-11-08 | アルディア バイオサイエンス，インク． | Compounds, compositions and methods for regulating uric acid levels |
| EP2432468A2 (en) * | 2009-05-20 | 2012-03-28 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
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Effective date of registration: 20181211 Address after: 225300 Pearl River Road, Yongan Town, Taizhou, Jiangsu Province, 108 Patentee after: Wang Yajun Address before: 528000 floor 5, Pu Lan Road, Chancheng District, Foshan, Guangdong. Patentee before: Zhang Yuanqiang |
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Effective date of registration: 20190731 Address after: Room 4030, 57 Guangda Road, Yuanshan Street Security Community, Longgang District, Shenzhen City, Guangdong Province Patentee after: Shenzhen Laibao Biotechnology Co., Ltd. Address before: 225300 No. 108 Mingzhu Avenue, Yonganzhou Town, Gaogang District, Taizhou City, Jiangsu Province Patentee before: Wang Yajun |
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Granted publication date: 20160817 Termination date: 20201027 |