CN104341365A - Halogenated triazole malonic acid compounds as well as preparation method and application thereof - Google Patents
Halogenated triazole malonic acid compounds as well as preparation method and application thereof Download PDFInfo
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- CN104341365A CN104341365A CN201410583853.2A CN201410583853A CN104341365A CN 104341365 A CN104341365 A CN 104341365A CN 201410583853 A CN201410583853 A CN 201410583853A CN 104341365 A CN104341365 A CN 104341365A
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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
Abstract
The invention relates to the field of medicines related to hyperuricemia and gout and in particular relates to urate transporter I (URAT1) inhibitors containing halogenated triazole malonic acid structures, a preparation method thereof, a medicine composition containing the URAT1 inhibitors and an application of the URAT1 inhibitors and the medicine composition to preparation of diabetes medicines. In a general formula, R is selected from halogen substituent.
Description
Technical field
The present invention relates to the pharmaceutical field that treatment hyperuricemia is relevant with gout.Specifically, the present invention relates to hyperuricemia and the medicative class of gout containing uric acid transporter body 1 (urate transporter 1, the URAT1) inhibitor of halo triazole propanedioic acid structure, preparation method, containing they pharmaceutical composition and in purposes pharmaceutically.
Background technology
Gout is a kind of chronic metabolic disease, and the pain being deposited on the positions such as joint with hyperuricemia and monosodium urate salt (MSU) and causing is for principal character, and major cause is purine metabolic disturbance and/or uric acid excretion disorder.According to estimates, current global patient with gout has more than 2,000 ten thousand.The medicine being used for the treatment of gout at present comprises for lenitive anti-inflammatory drug (as colchicine etc.), suppresses uricogenesis medicine (xanthine oxidase inhibitor being representative with allopurinol and Febuxostat), thick uric acid excretion medicine (the uric acid excretion medicine being representative with probenecid, sulfinpyrazone, benzbromarone and losartan) and uriKoxidase (with pegloticase for representative).There is the toxic side effect of different degree in these medicines, as benzbromarone has the danger causing explosive hepatitis, allopurinol has liver and the untoward reaction such as bone marrow toxicity and transformation reactions, etc.
Lesinurad (RDEA 594) be a kind of developed by Ardea company can suppress uric acid transporter body (urate transporter 1 in kidney, URAT1) discharged the oral pharmaceutical of uric acid in blood by the approach of urine, be in III phase clinical stage at present.The antiviral RDEA806 that Lesinurad is researched and developed by Valeant company the earliest develops.The right of ownership of present Lesinurad is at present because Ardea company is belonged to Astra Zeneca by purchasing.
The invention discloses the URAT1 inhibitor of a class containing halo triazole propanedioic acid structure, these compounds can be used for the medicine preparing treatment hyperuricemia and gout.
Summary of the invention
An object of the present invention is to provide one and there is excellent activity, there is a compounds of general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula (I) has following structural formula:
Wherein, R is selected from halogenic substituent.
The compound of preferred formula (I) has following structure,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per and alpha-brominated dimethyl malonate react in the presence of a base, obtain compound IV; Compound IV is obtained by reacting compound V with Sodium Nitrite and dichloro acetic acid in bromofom; Compound V is hydrolyzed in the basic conditions and obtains Compound I.
Compound of Formula I of the present invention has the restraining effect of URAT1, can be used as the medicine of effective constituent for the preparation of hyperuricemia and gout.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
A. the synthesis of compound IV-1
6.42g (20mmol) Compound II per-1 and 4.22g (20mmol) compound III are dissolved in the DMF of 100mL drying, and stirred at ambient temperature adds 8.29g (60mmol) solid K
2cO
3, then reaction mixture at room temperature stirs, until TLC follows the tracks of find that reaction completes (within general 12h).Reaction mixture pours in 400mL frozen water, stirs, and uses the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the salt water washing of 100mL 5%, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=474 ([M+Na]
+).
B. the synthesis of compound V-1
5.41g (12mmol) compound IV-1 is dissolved in 30mL bromofom, stirred at ambient temperature, adds 3.45g (50mmol) NaNO
2with 3.00g benzyl triethyl ammonium bromide, then add 6.45g (50mmol) dichloro acetic acid.Gained mixture at room temperature stirs, until TLC follows the tracks of find that reaction completes (within general 12h).Reaction mixture pours in 300mL frozen water, stirs, and uses the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the Na of 100mL 2% successively
2s
2o
3the salt water washing of solution and 100mL 5%, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=538 ([M+Na]
+).
C. the synthesis of Compound I-1
4.08g (8mmol) compound V-1 is dissolved in 30mL methyl alcohol, and stirred at ambient temperature adds the LiOH solution of 3mL10%, gained mixture stirred at ambient temperature, until TLC follows the tracks of find that reaction completes (within general 3h).Reaction mixture pours in 200mL frozen water, stirs, and uses concentrated hydrochloric acid to regulate the CH of pH=2-3,100mL × 3
2cl
2extraction, merges extraction phase, uses the salt water washing of 100mL 5%, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I-1, white-yellowish solid, ESI-MS, m/z=486,488 ([M-H]
-).
embodiment 2-4
With reference to embodiment 1 operation steps, synthesize compound listed in Table.
embodiment 5
The IC that compound of the present invention and related compound suppress URAT1
50be worth the similar method recorded according to document and measure (in US2014/0005136 embodiment 12).
Build the cell strain of stably express humanization URAT1 transporter: be subcloned into the plasmid pCMV6/neo (Origene) of eukaryotic expression from plasmid pCMV6-XL-5 (Origene) by humanization URAT1 gene (SLC22A112).Gene sequencing confirms humanization URAT1 consistent with the information recorded in gene pool (NM_144585.2).HEK293 human embryonic kidney cell (ATCC#CRL-1573) in EMEM tissue culture medium at the CO of 5%
2cultivate with in the air atmosphere of 95%.L2000 type transfection agents (Invitrogene) is used to be transfected on HEK293 cell by pCMV6/Neo/URAT1.After 24 hours, transfected cell being assigned to diameter is in the tissue culture dishes of 10cm, continued growth one day, then substratum is replaced by the fresh substratum containing 0.5mg/mL G418 (Gibco).After 8 days, select and collect resistance bacterium colony, and right with its test
14the transport activity of the uric acid of C-mark.By HEK293/URAT1 cell with 75, the density in 000/ hole is planted on 96 orifice plates that cover in poly-D-Lys.
These cells grow overnight at 37 DEG C in incubator, then under cool to room temperature, nutrient solution wherein uses the scavenging solution washing in 250 μ L/ holes once (10mMHEPES of 125mM Sunmorl N 60S, pH=7.3).Testing compound or blank be added to containing 40 μMs
14c-marks in the damping fluid of uric acid (54mCi/mmol), described damping fluid contains 125mM Sunmorl N 60S, 4.8mM Potassium Gluconate, 1.2mM potassium primary phosphate, 1.2mM magnesium sulfate, 1.3mM calglucon, 5.6mM glucose, 25mM HEPES, final pH=7.3.96 orifice plates at room temperature cultivate 10 minutes, then respectively clean three times with the above-mentioned scavenging solution in 50 μ L/ holes and 250 μ L/ holes successively.96 orifice plates add Microscint 20 type liquid and dodges agent, plank is overnight incubation at 45 DEG C, then reading on TopCount Plate Reader, and calculates IC accordingly
50.
Shown in the following list of result:
Part of compounds of the present invention is to the IC of URAT1
50value
| Compound | IC 50(hURAT1,nM) |
| Lesinurad | 22.4 |
| I-1 | 19.7 |
| I-2 | 25.1 |
| I-3 | 22.8 |
| I-4 | 29.0 |
Above-mentioned IC
50measurement result show, the compounds of this invention is strong URAT1 inhibitor, can be used for preparing treatment hyperuricemia and the medicine of gout.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from halogenic substituent.
2. the compound of Formula I that defines of claim 1, is selected from following compounds,
。
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per and alpha-brominated dimethyl malonate react in the presence of a base, obtain compound IV; Compound IV is obtained by reacting compound V with Sodium Nitrite and dichloro acetic acid in bromofom; Compound V is hydrolyzed in the basic conditions and obtains Compound I.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment hyperuricemia and gout medicine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410583853.2A CN104341365A (en) | 2014-10-27 | 2014-10-27 | Halogenated triazole malonic acid compounds as well as preparation method and application thereof |
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|---|---|---|---|
| CN201410583853.2A CN104341365A (en) | 2014-10-27 | 2014-10-27 | Halogenated triazole malonic acid compounds as well as preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102186832A (en) * | 2008-09-04 | 2011-09-14 | 亚德生化公司 | Compounds, compositions and methods of using same for modulating uric acid levels |
| CN102643241A (en) * | 2007-11-27 | 2012-08-22 | 亚德生化公司 | Compounds and compositions and methods of use |
-
2014
- 2014-10-27 CN CN201410583853.2A patent/CN104341365A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643241A (en) * | 2007-11-27 | 2012-08-22 | 亚德生化公司 | Compounds and compositions and methods of use |
| CN102186832A (en) * | 2008-09-04 | 2011-09-14 | 亚德生化公司 | Compounds, compositions and methods of using same for modulating uric acid levels |
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Application publication date: 20150211 |