CN104311445B - Naphthalene-ring containing succinamide derivative, Preparation Method And The Use - Google Patents
Naphthalene-ring containing succinamide derivative, Preparation Method And The Use Download PDFInfo
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- CN104311445B CN104311445B CN201410501872.6A CN201410501872A CN104311445B CN 104311445 B CN104311445 B CN 104311445B CN 201410501872 A CN201410501872 A CN 201410501872A CN 104311445 B CN104311445 B CN 104311445B
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Abstract
The present invention relates to the pharmaceutical field relevant to hyperuricemia and gout.Specifically, the present invention relates to uric acid transporter body 1 inhibitor of the naphthalene-ring containing succinamide structure of a class, its preparation method and preparing the application in diabetes medicament containing their pharmaceutical composition and they.
wherein, R
1be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl; R
2be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl.
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 (uratetransporter1, 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 (RDEA594) be a kind of developed by Ardea company can suppress uric acid transporter body (uratetransporter1 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 AstraZeneca 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 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.
Another object of the present invention is to provide compound containing general formula I 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 H, C
1-C
5alkyl, C
3-C
6cycloalkyl;
R
2be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl.
Preferred: R
1be selected from H, C
1-C
4alkyl, C
3-C
4cycloalkyl;
R
2be selected from H, C
1-C
4alkyl, C
3-C
4cycloalkyl.
The compound of preferred formula I has following structure,
。
More preferably the compound of general formula I has following structure,
。
Be selected from following compounds further,
。
Compound of Formula I of the present invention is synthesized by following route:
。
Compound II per with monomethyl succinate III condensation under condensing agent exists, obtain compound IV; Compound IV is hydrolyzed in the presence of a base and obtains compound V; Compound V and compound R
2nH (VI) condensation under condensing agent exists, obtains product I.Described condensing agent is selected from DCC, EDC, TBTU and HATU etc.Described R
1, R
2definition as previously mentioned.
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.
embodiment 1
。
A. the synthesis of compound IV-1
3.14g (20mmol) Compound II per-1 and 2.64g (20mmol) compound III are dissolved in the THF of 50mL drying, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 4.13g (20mmol) and DMAP (DMAP) 0.61g (5mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 300mL frozen water, stirs, and uses the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100mL1% and the salt water washing of 100mL5% 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=294 ([M+Na]
+).
B. the synthesis of compound V-1
Compound IV-14.06g (15mmol) is dissolved in 30mL anhydrous methanol, stirred at ambient temperature, adds the LiOH solution of 3mL10%, then continues under room temperature to stir, until TLC detection reaction completes (within 5h).
Reaction mixture is poured in 200mL frozen water, stirs, regulates pH=2-3 with concentrated hydrochloric acid.Use the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the salt water washing of 100mL5%, 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=258 ([M-H]
-).
C. the synthesis of Compound I-1
2.59g (10mmol) compound V-1 and 0.73g (10mmol) compound VI-1 is dissolved in the THF of 30mL drying, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 2.06g (10mmol) and DMAP (DMAP) 0.61g (5mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 200mL frozen water, stirs, and uses the CH of 70mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100mL1% and the salt water washing of 100mL5% 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=330 ([M+NH
4]
+).
embodiment 2
。
A. the synthesis of compound IV-2
3.66g (20mmol) Compound II per-2 and 2.64g (20mmol) compound III are dissolved in the THF of 50mL drying, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 4.13g (20mmol) and DMAP (DMAP) 0.61g (5mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 300mL frozen water, stirs, and uses the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100mL1% and the salt water washing of 100mL5% 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-2, ESI-MS, m/z=320 ([M+Na]
+).
B. the synthesis of compound V-2
Compound IV-24.45g (15mmol) is dissolved in 30mL anhydrous methanol, stirred at ambient temperature, adds the LiOH solution of 3mL10%, then continues under room temperature to stir, until TLC detection reaction completes (within 5h).
Reaction mixture is poured in 200mL frozen water, stirs, regulates pH=2-3 with concentrated hydrochloric acid.Use the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses the salt water washing of 100mL5%, 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-2, ESI-MS, m/z=282 ([M-H]
-).
C. the synthesis of Compound I-2
2.83g (10mmol) compound V-2 and 0.57g (10mmol) compound VI-2 is dissolved in the THF of 30mL drying, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 2.06g (10mmol) and DMAP (DMAP) 0.61g (5mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 200mL frozen water, stirs, and uses the CH of 70mL × 3
2cl
2extraction, merges extraction phase, uses the dilute hydrochloric acid of 100mL1% and the salt water washing of 100mL5% 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-2, white-yellowish solid, ESI-MS, m/z=340 ([M+NH
4]
+).
embodiment 3-12
With reference to the operation steps of embodiment 1,2, prepare compound listed in Table:
。
embodiment 13
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 0.5mg/mLG418 (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 (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, 25mMHEPES, 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 Microscint20 type liquid and dodges agent, plank is overnight incubation under 45 ° of C, then reading on TopCountPlateReader, 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 (7)
1. there is the compound of general formula I,
Wherein, R
1be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl;
R
2be selected from H, C
1-C
5alkyl, C
3-C
6cycloalkyl.
2. the compound with general formula I that claim 1 defines,
Wherein, R
1be selected from H, C
1-C
4alkyl, C
3-C
4cycloalkyl;
R
2be selected from H, C
1-C
4alkyl, C
3-C
4cycloalkyl.
3. the compound of Formula I that defines of claim 2, is selected from following compounds,
4. the compound of Formula I that defines of claim 3, is selected from following compounds further,
5. the compound of Formula I that defines of claim 4, is selected from following compounds further,
6. synthesize the method for the compound of the general formula I that any one of claim 1-4 defines:
Compound II per and monomethyl succinate III condensation under condensing agent exists, obtain compound IV; Compound IV is hydrolyzed in the presence of a base and obtains compound V; Compound V and compound R
2nH (VI) condensation under condensing agent exists, obtains product I; Described condensing agent is selected from DCC, EDC, TBTU and HATU; Described R
1, R
2definition as described in any one of claim 1-4.
7. the compound of Formula I that any one of claim 1-5 defines is preparing the application in treatment hyperuricemia and gout medicine.
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|---|---|---|---|
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|---|---|---|---|
| CN201410501872.6A CN104311445B (en) | 2014-09-27 | 2014-09-27 | Naphthalene-ring containing succinamide derivative, Preparation Method And The Use |
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|---|---|
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| CN104311445B true CN104311445B (en) | 2016-04-13 |
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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 CN201410501872.6A patent/CN104311445B/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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