CN104311444B - Nitro replaces succinamide derivative, the Preparation Method And The Use of naphthalene nucleus - Google Patents
Nitro replaces succinamide derivative, the Preparation Method And The Use of naphthalene nucleus Download PDFInfo
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- CN104311444B CN104311444B CN201410501871.1A CN201410501871A CN104311444B CN 104311444 B CN104311444 B CN 104311444B CN 201410501871 A CN201410501871 A CN 201410501871A CN 104311444 B CN104311444 B CN 104311444B
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Abstract
The present invention relates to the drug world relevant to hyperuricemia and gout. Particularly, the present invention relates to one class nitro replace naphthalene nucleus succinamide structure uric acid transporter body 1 inhibitor, its preparation method and the pharmaceutical composition that contains them and they are in the application of preparing in diabetes medicament.<b>(I</b><b>)</b>Wherein, R1Be selected from-NO2、-CN；R2Be selected from H, C1-C5Alkyl, C3-C6Cycloalkyl.
Description
Technical field
The present invention relates to treat the drug world that hyperuricemia is relevant with gout. Particularly, the present invention relates to heightThe medicative class of uricacidemia and gout replaces the uric acid transporter body 1 of the succinamide derivative of naphthalene nucleus containing nitro(uratetransporter1, URAT1) inhibitor, preparation method, the pharmaceutical composition that contains them and pharmaceuticallyPurposes.
Background technology
Gout is a kind of chronic metabolic disease, is deposited on the portions such as joint with hyperuricemia and monosodium urate salt (MSU)Position and the pain that causes is principal character, main cause is purine metabolic disturbance and/or uric acid excretion disorder. According to estimates, currentWhole world patient with gout has more than 2,000 ten thousand. The medicine that is used for the treatment of at present gout comprises for lenitive anti-inflammatory drug (as the autumnTazettine etc.), suppress uric acid generating medicine (xanthine oxidase inhibitor taking Allopurinol and Febuxostat as representative), urine slightlyAcid excretion medicine (the uric acid excretion medicine taking probenecid, sulfinpyrazone, Benzbromarone and Losartan as representative) and uricase (withPegloticase is representative). There is the toxic and side effect of different degree in these medicines, causes explosive liver as Benzbromarone hasScorching danger, Allopurinol has the bad reaction such as liver and bone marrow toxicity and allergy, etc.
Lesinurad (RDEA594) be a kind of developed by Ardea company can suppress uric acid transporter body in kidney(uratetransporter1, URAT1) and discharge the oral drugs of uric acid in blood by the approach of urine, locates at presentIn III phase clinical stage. The antiviral drugs RDEA806 that Lesinurad is researched and developed by Valeant company the earliest develops. ExistingIn the ownership of Lesinurad at present because Ardea company is purchased and is belonged to AstraZeneca.
The invention discloses a class nitro replace naphthalene nucleus the URAT1 inhibitor of succinamide derivative, these changesCompound can be used for the medicine of preparation 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 for preparing the compound with general formula I.
A further object of the present invention is to provide the compound that contains general formula I as active ingredient, and one or moreThe Pharmaceutical composition of pharmaceutically acceptable carrier, excipient or diluent, and the application aspect gout in treatment.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The present invention have the compound of general formula I and pharmaceutically acceptable prodrug ester there is following structural formula:
(I)
Wherein, R1Be selected from-NO2、-CN；
R2Be selected from H, C1-C5Alkyl, C3-C6Cycloalkyl.
Preferred: R1Be selected from-NO2、-CN；
R2Be selected from C1-C4Alkyl, C3-C4Cycloalkyl.
The compound of preferred formula I has following structure,
。
More preferably the compound of general formula I has following structure,
。
Compound of Formula I of the present invention is synthetic by following route:
。
Compound I I condensation under condensing agent exists with monomethyl succinate III, obtains compound IV; Compound IV existsAlkali exists lower hydrolysis to obtain compound V; Compound V and compound R2NH (VI) condensation under condensing agent exists, obtains productI. Described condensing agent is selected from DCC, EDC, TBTU and HATU etc. Described R1、R2Definition as previously mentioned.
Compound of Formula I of the present invention has the inhibitory action of URAT1, can be used as active ingredient for the preparation of high lithemiaThe medicine of mass formed by blood stasis and gout. The activity of compound of Formula I of the present invention is to verify by receptor binding assays.
Compound of Formula I of the present invention is effective in quite wide dosage range. The dosage that take for example every day approximatelyWithin the scope of 1mg-500mg/ people, be divided into once or administration for several times. The actual dosage of taking compound of Formula I of the present invention can be byDoctor decides according to relevant situation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated. It should be noted that, following embodiment be only forIllustrate, and not for limiting the present invention. The various variations that those skilled in the art's training centre according to the present invention is made all shouldWithin the desired protection domain of the application's claim.
Embodiment 1
。
A. compound IV-1 is synthetic
It is dry that 3.76g (20mmol) Compound I I-1 and 2.64g (20mmol) compound III are dissolved in 50mLIn THF, the cooling lower stirring of ice-water bath, adds dicyclohexyl carbodiimide (DCC) 4.13g (20mmol) and 4-diformazan ammoniaYl pyridines (DMAP) 0.61g (5mmol), then stirs under room temperature, until TLC detection reaction completes (in 12h). ReactionMixture is poured in 300mL frozen water, stirs, and uses the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses successivelyThe salt water washing of the watery hydrochloric acid of 100mL1% and 100mL5%, anhydrous sodium sulfate drying. Suction filtration is removed drier, and filtrate is being revolvedTurn evaporate to dryness on evaporimeter, the residue obtaining uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=325([M+Na]+)。
B. compound V-1's is synthetic
Compound IV-14.53g (15mmol) is dissolved in 30mL absolute methanol, under room temperature, stirs, and adds 3mL10% LiOH solution, then continues under room temperature to stir, until TLC detection reaction completes (in 5h).
Reactant mixture is poured in 200mL frozen water, stirs, and regulates pH=2-3 with concentrated hydrochloric acid. Use 100mL ×3 CH2Cl2Extraction, merges extraction phase, uses the salt water washing of 100mL5%, anhydrous sodium sulfate drying. Suction filtration is removed dryAgent, filtrate is evaporate to dryness on Rotary Evaporators, and the residue obtaining uses column chromatography purification (short column), obtains compound V-1, lightYellow solid, ESI-MS, m/z=287 ([M-H]-)。
C. Compound I-1 is synthetic
It is dry that 2.88g (10mmol) compound V-1 and 0.73g (10mmol) compound VI-1 are dissolved in 30mLIn THF, the cooling lower stirring of ice-water bath, adds dicyclohexyl carbodiimide (DCC) 2.06g (10mmol) and 4-diformazan ammoniaYl pyridines (DMAP) 0.61g (5mmol), then stirs under room temperature, until TLC detection reaction completes (in 12h). ReactionMixture is poured in 200mL frozen water, stirs, and uses the CH of 70mL × 32Cl2Extraction, merges extraction phase, uses successivelyThe salt water washing of the watery hydrochloric acid of 100mL1% and 100mL5%, anhydrous sodium sulfate drying. Suction filtration is removed drier, and filtrate is being revolvedTurn evaporate to dryness on evaporimeter, the residue obtaining uses column chromatography purification, obtains Compound I-1, white-yellowish solid. ESI-MS, m/z=361([M+NH4]+)。
Embodiment 2-13
With reference to the operating procedure of embodiment 1, prepare the listed compound of following table:
Embodiment 9
The IC that compound of the present invention and related compound suppress URAT150It is similar that value is recorded according to documentMethod is measured (embodiment 12 in US2014/0005136). Shown in the following list of result.
Build the cell line of stably express humanization URAT1 transporter: by humanization URAT1 gene (SLC22A112) fromPlasmid pCMV6-XL-5 (Origene) is subcloned on the plasmid pCMV6/neo (Origene) of eukaryotic expression. Gene sequencingConfirm humanization URAT1 consistent with the information recording in gene pool (NM_144585.2). HEK293 human embryonic kidney cell(ATCC#CRL-1573) in EMEM tissue culture medium at 5% CO2With in 95% air atmosphere, cultivate. Use L2000 typeTransfection agents (Invitrogene) is transfected into pCMV6/Neo/URAT1 on HEK293 cell. After 24 hours, by transfected thinIt is organizing in culture dish of 10cm that born of the same parents assign to diameter, and continued growth one day, is then replaced by culture medium to contain 0.5mg/mLThe fresh culture medium of G418 (Gibco). After 8 days, select and collect drug resistance bacterium colony, and right with its test14The urine of C-markThe transport activity of acid. HEK293/URAT1 cell is planted to 96 orifice plates that cover in poly-D-Lys with the density in 75,000/ holesOn.
These cells grow overnight under 37 ° of C in incubator, then, under cool to room temperature, nutrient solution wherein uses 250Once (10mMHEPES of 125mM gluconic acid sodium salt, pH=7.3) of cleaning fluid washing in μ L/ hole. By testing compound orPerson's blank is added to and contains 40 μ M's14In the buffer solution of C-mark uric acid (54mCi/mmol), described buffer solution contains 125MM gluconic acid sodium salt, 4.8mM K-IAO, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconae,5.6mM glucose, 25mMHEPES, final pH=7.3. 96 orifice plates are at room temperature cultivated 10 minutes, then use successively 50 μThe each cleaning three times of above-mentioned cleaning fluid in L/ hole and 250 μ L/ holes. On 96 orifice plates, add Microscint20 type liquid to dodge agent, plateSon overnight incubation under 45 ° of C, then reading on TopCountPlateReader, and calculate accordingly IC50. Result is as followingShown in table:
。
Above-mentioned IC50Measurement result show, compound of the present invention all shows good URAT1 inhibitor, Ke YiyongPrepare the medicine for the treatment of hyperuricemia and gout.
Claims (5)
1. there is the compound of general formula I structure,
Wherein, R1Be selected from-NO2、-CN；
R2Be selected from H, C1-C5Alkyl, C3-C6Cycloalkyl.
2. the defined compound with general formula I of claim 1,
Wherein, R1Be selected from-NO2、-CN；
R2Be selected from C1-C4Alkyl, C3-C4Cycloalkyl.
3. the defined compound of Formula I of claim 2, is selected from following compounds,
4. the defined compound of Formula I of claim 3, is further selected from following compounds,
5. the defined compound of Formula I of claim 1-4 any one is aspect preparation treatment hyperuricemia and gout medicineApplication.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3632646A (en) * | 1967-05-25 | 1972-01-04 | Uniroyal Inc | Succinamides |
| JPS5572145A (en) * | 1978-11-22 | 1980-05-30 | Nippon Soda Co Ltd | Enzyme-adsorbent and purification of enzyme |
| CN103588660A (en) * | 2013-11-18 | 2014-02-19 | 中国医学科学院生物医学工程研究所 | Novel acyl aniline compound and application thereof |
| WO2014065413A1 (en) * | 2012-10-26 | 2014-05-01 | 日本たばこ産業株式会社 | Triazole-isoxazole compound and medical use thereof |
| WO2014131374A1 (en) * | 2013-02-28 | 2014-09-04 | Centro De Neurociencias De Cuba (Neuronic) | Chemical chaperonins as novel molecular modulators of beta protein aggregation present in conformational diseases |
-
2014
- 2014-09-27 CN CN201410501871.1A patent/CN104311444B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3632646A (en) * | 1967-05-25 | 1972-01-04 | Uniroyal Inc | Succinamides |
| JPS5572145A (en) * | 1978-11-22 | 1980-05-30 | Nippon Soda Co Ltd | Enzyme-adsorbent and purification of enzyme |
| WO2014065413A1 (en) * | 2012-10-26 | 2014-05-01 | 日本たばこ産業株式会社 | Triazole-isoxazole compound and medical use thereof |
| WO2014131374A1 (en) * | 2013-02-28 | 2014-09-04 | Centro De Neurociencias De Cuba (Neuronic) | Chemical chaperonins as novel molecular modulators of beta protein aggregation present in conformational diseases |
| CN103588660A (en) * | 2013-11-18 | 2014-02-19 | 中国医学科学院生物医学工程研究所 | Novel acyl aniline compound and application thereof |
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Effective date of registration: 20181022 Address after: 226400 55 group three, Fang Quan village, dugong Town, Rudong, Nantong, Jiangsu Patentee after: Mao Tingting Address before: 528000 floor 5, Pu Lan Road, Chancheng District, Foshan, Guangdong. Patentee before: Zhang Yuanqiang |