CN104311443A - Naphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives - Google Patents
Naphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives Download PDFInfo
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- CN104311443A CN104311443A CN201410501870.7A CN201410501870A CN104311443A CN 104311443 A CN104311443 A CN 104311443A CN 201410501870 A CN201410501870 A CN 201410501870A CN 104311443 A CN104311443 A CN 104311443A
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- 0 *NC(CCC(Nc(c1c2cccc1)ccc2O)=[U])=O Chemical compound *NC(CCC(Nc(c1c2cccc1)ccc2O)=[U])=O 0.000 description 1
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Abstract
The invention relates to the field of medicines related to hyperuricemia and gout, and particularly relates to urate transporter 1 inhibitors having structures of naphthalene-ring-containing butanedioic acid amides, a preparing method thereof, pharmaceutical compositions containing the inhibitors and applications of the inhibitors in preparation of medicines for diabetes. A formula (I) is shown in the specification, wherein R1 is selected from C1-C5 alkyl, and R2 is selected from H, C1-C5 alkyl and C3-C6 cycloalkyl.
Description
Technical field
The present invention relates to the pharmaceutical field that treatment hyperuricemia is relevant with gout.Specifically, the present invention relates to uric acid transporter body 1 (urate transporter 1, the URAT1) inhibitor to hyperuricemia and the naphthalene-ring containing succinamide derivative of the medicative class of gout, 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 the naphthalene-ring containing succinamide derivative of a class, 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 general formula
ia compounds.
Another object of the present invention is to provide preparation and has general formula
ithe method of compound.
Another object of the present invention is to provide containing general formula
icompound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment gout.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
the present invention have general formula I compound and pharmaceutically acceptable prodrug ester there is following structural formula:
( I )
Wherein, R
1be selected from C
1-C
5alkyl;
R
2be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl.
preferably: R
1be selected from C
1-C
3alkyl;
R
2be selected from C
1-C
4alkyl, C
3-C
4cycloalkyl.
the compound of preferred formula I has following structure,
。
further, the compound of preferred formula I has following structure,
。
compound of Formula I of the present invention is synthesized by following route:
。
Compound
iIwith with monomethyl succinate
iIIcondensation under condensing agent exists, obtains compound
iV; Compound
iVhydrolysis obtains compound in the presence of a base
v; Compound
vwith compound R
2nH (
vI) condensation under condensing agent exists, obtain product
i.Described condensing agent is selected from DCC, EDC, TBTU and HATU etc.Described R
1, R
2definition as previously mentioned.
General formula of the present invention
icompound has the restraining effect of URAT1, can be used as the medicine of effective constituent for the preparation of hyperuricemia and gout.General formula of the present invention
ithe activity of compound is verified by receptor binding assays.
General formula of the present invention
icompound is effective in quite wide dosage range.The dosage taken such as every day, within the scope of 1 mg-500 mg/ people, is divided into once or administration for several times.Actually take general formula of the present invention
ithe dosage of compound 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.
embodiment 1
。
A. compound
iV-1synthesis
3.46g (20 mmol) compound
iI-1with 2.64 g (20 mmol) compound
iIIbe dissolved in the THF of 50 mL dryings, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 4.13 g (20 mmol) and DMAP (DMAP) 0.61 g (5 mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 300 mL frozen water, stirs, uses the CH of 100 mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100 mL 1% and the salt water washing of 100 mL 5% successively, 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=310 ([M+Na]
+).
B. compound
v-1synthesis
Compound
iV-14.30g (15 mmol) is dissolved in 30 mL anhydrous methanols, and stirred at ambient temperature adds the LiOH solution of 3 mL 10%, then continues under room temperature to stir, until TLC detection reaction completes (within 5h).
Reaction mixture is poured in 200 mL frozen water, stirs, regulates pH=2-3 with concentrated hydrochloric acid.Use the CH of 100 mL × 3
2cl
2extraction, merges extraction phase, uses the salt water washing of 100 mL 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 (short column), obtains compound
v-1, white solid, ESI-MS,
m/z=272 ([M-H]
-).
C. compound
i-1synthesis
2.73g (10 mmol) compound
v-1with 0.73 g (10 mmol) compound
vI-1be dissolved in the THF of 30 mL dryings, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 2.06 g (10 mmol) and DMAP (DMAP) 0.61 g (5 mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 200 mL frozen water, stirs, uses the CH of 70 mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100 mL 1% and the salt water washing of 100 mL 5% successively, 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 solid.ESI-MS,
m/z = 346([M+NH
4]
+)。
embodiment 2-9
With reference to the operation steps of embodiment 1, prepare compound listed in Table.
embodiment 10
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).Shown in the following list of result.
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 0.5 mg/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 under 37 ° of C in incubator, then under cool to room temperature, nutrient solution wherein uses the scavenging solution washing in 250 μ L/ holes once (10 m MHEPES of 125 mM Sunmorl N 60Ss, 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 125 mM Sunmorl N 60Ss, 4.8 mM Potassium Gluconates, 1.2 mM potassium primary phosphates, 1.2 mM magnesium sulfate, 1.3 mM calglucons, 5.6 mM glucose, 25 mM 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 under 45 ° of C, then reading on TopCount Plate Reader, and calculates IC accordingly
50.Shown in the following list of result:
。
Above-mentioned IC
50measurement result show, compound of the present invention all shows as strong URAT1 inhibitor, can be used for preparing treatment hyperuricemia and the medicine of gout.
Claims (6)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
( I )
Wherein, R
1be selected from C
1-C
5alkyl;
R
2be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl.
2. the compound with general formula I that claim 1 defines and pharmaceutically acceptable prodrug ester,
Wherein, R
1be selected from C
1-C
3alkyl;
R
2be selected from C
1-C
4alkyl, C
3-C
4cycloalkyl.
3. the general formula that defines of claim 2
icompound, is selected from following compounds,
。
4. the general formula that defines of claim 3
icompound, is selected from following compounds further,
。
5. synthesize the general formula that claim 1-4 defines
ithe method of compound:
Compound
iIwith with monomethyl succinate
iIIcondensation under condensing agent exists, obtains compound
iV; Compound
iVhydrolysis obtains compound in the presence of a base
v; Compound
vwith compound R
2nH (
vI) condensation under condensing agent exists, obtain product
i; Described condensing agent is selected from DCC, EDC, TBTU and HATU; Described R
1, R
2definition as arbitrary in claim 1-4 as described in.
6. the compound of Formula I that defines of claim 1-4 and the pharmaceutically application of acceptable prodrug ester in preparation treatment hyperuricemia and gout medicine thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410501870.7A CN104311443B (en) | 2014-09-27 | 2014-09-27 | The naphthalene-ring containing succinamide derivative of one class, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410501870.7A CN104311443B (en) | 2014-09-27 | 2014-09-27 | The naphthalene-ring containing succinamide derivative of one class, Preparation Method And The Use |
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| Publication Number | Publication Date |
|---|---|
| CN104311443A true CN104311443A (en) | 2015-01-28 |
| CN104311443B CN104311443B (en) | 2016-03-09 |
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ID=52366792
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|---|---|---|---|
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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 CN201410501870.7A patent/CN104311443B/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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| Publication number | Publication date |
|---|---|
| CN104311443B (en) | 2016-03-09 |
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Effective date of registration: 20181018 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 |