CN104341361A - Cyano-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof - Google Patents
Cyano-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof Download PDFInfo
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- CN104341361A CN104341361A CN201410582687.4A CN201410582687A CN104341361A CN 104341361 A CN104341361 A CN 104341361A CN 201410582687 A CN201410582687 A CN 201410582687A CN 104341361 A CN104341361 A CN 104341361A
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- compound
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- urat1
- triazolesulfonylmalonic
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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
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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 cyano-substituted triazolesulfonylmalonic 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. A structure of the URAT1 inhibitors is shown in the specification.
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 the triazole sulfinyl propanedioic acid structure that hyperuricemia and the medicative a kind of itrile group of gout replace, preparation method, containing it 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 triazole sulfinyl propanedioic acid structure that a kind of nitrile group-containing replaces, 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 the compound of formula I.
Another object of the present invention is to provide the method that preparation has the compound of 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 formula I has following structural formula:
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 formula I of the present invention is verified by receptor binding assays.
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 formula I 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
A. the synthesis of compound IV
5.34g (20mmol) Compound II per 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, white solid, ESI-MS, m/z=420 ([M+Na]
+).
B. the synthesis of compound V
4.76g (12mmol) compound IV 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, white solid, ESI-MS, m/z=484 ([M+Na]
+).
C. the synthesis of compound VI
3.68g (8mmol) compound V is dissolved in 30mL methyl alcohol, and stirred at ambient temperature adds the LiOH solution of 3mL 10%, 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 VI, white solid, ESI-MS, m/z=433,431 ([M-H]
-).
D.
the synthesis of Compound I
2.59g (6mmol) compound VI is dissolved in 10mL CH
2cl
2in, stir, add 1.24g (7.2mmol) metachloroperbenzoic acid (mCPBA), stirred at ambient temperature 5h hour.Reaction mixture pours in 200mL frozen water, stirs, the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses 100mL 2%Na successively
2s
2o
3the saturated NaHCO of solution, 100mL
3with 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, white solid, ESI-MS, m/z=449,447 ([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 prepared be all the applicant find 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 per-2 and 4.22g (20mmol) compound III-2 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-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, 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-2, white solid, ESI-MS, m/z=459 ([M+Na]
+).
C. the synthesis of compound VI-2
3.48g (8mmol) compound V-2 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 VI-2, white solid, ESI-MS, m/z=406,408 ([M-H]
-).
D.
compound I-2
synthesis
2.44g (6mmol) compound VI is dissolved in 10mL CH
2cl
2in, stir, add 1.24g (7.2mmol) metachloroperbenzoic acid (mCPBA), stirred at ambient temperature 5h hour.Reaction mixture pours in 200mL frozen water, stirs, the CH of 100mL × 3
2cl
2extraction, merges extraction phase, uses 100mL 2%Na successively
2s
2o
3the saturated NaHCO of solution, 100mL
3with 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-2, white solid, ESI-MS, m/z=424,422 ([M-H]
-).
embodiment 3
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 |
| The compounds of this invention I | 14.0 |
| Control compounds I-2 | 30.7 |
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 (3)
1. there is the compound of formula I structure,
2. synthesize the method for the compound of formula I described in claim 1:
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 VI; Compound VI and 1 equivalent is oxidizing obtains Compound I.
3. the purposes of compound described in claim 1 in preparation treatment hyperuricemia and gout medicine.
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|---|---|---|---|
| CN201410582687.4A CN104341361B (en) | 2014-10-27 | 2014-10-27 | Cyano-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof |
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|---|---|---|---|
| CN201410582687.4A CN104341361B (en) | 2014-10-27 | 2014-10-27 | Cyano-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof |
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| Publication Number | Publication Date |
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| CN104341361A true CN104341361A (en) | 2015-02-11 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101083987A (en) * | 2004-08-25 | 2007-12-05 | 阿迪亚生命科学公司 | S-tryazolyl alpha,-mercaptoacetanliides as inhibitors of HIV reverse transcriptase |
| 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 |
| WO2014008295A1 (en) * | 2012-07-03 | 2014-01-09 | Ardea Biosciences, Inc. | Manufacture of 2- (5- bromo-4 (-cyclopropylnaphthalen-1-yl) -4h-1,2,4-triazol-3-ylthio) acetic acid |
-
2014
- 2014-10-27 CN CN201410582687.4A patent/CN104341361B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101083987A (en) * | 2004-08-25 | 2007-12-05 | 阿迪亚生命科学公司 | S-tryazolyl alpha,-mercaptoacetanliides as inhibitors of HIV reverse transcriptase |
| EP2402011A1 (en) * | 2004-08-25 | 2012-01-04 | Ardea Biosciences, Inc. | Intermediates in the synthesis of S-triazolyl alpha-mercaptoacetanildes as inhibitors of HIV reverse transcriptase |
| 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 |
| WO2014008295A1 (en) * | 2012-07-03 | 2014-01-09 | Ardea Biosciences, Inc. | Manufacture of 2- (5- bromo-4 (-cyclopropylnaphthalen-1-yl) -4h-1,2,4-triazol-3-ylthio) acetic acid |
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| CN104341361B (en) | 2017-01-11 |
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Effective date of registration: 20181226 Address after: Room 204-209, Science and Technology Entrepreneurship Park, Jiefangnan Road Mining University, Xuzhou City, Jiangsu Province, 221000 Patentee after: Li Gui Address before: 528000 floor 5, Pu Lan Road, Chancheng District, Foshan, Guangdong. Patentee before: Zhang Yuanqiang |
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Effective date of registration: 20191031 Address after: 314100 room 427, No.16 Fuxing Avenue, Xitang Town, Jiashan County, Jiaxing City, Zhejiang Province Patentee after: Zhejiang Xitang Industry Co., Ltd Address before: Room 204-209, Science and Technology Entrepreneurship Park, Jiefangnan Road Mining University, Xuzhou City, Jiangsu Province, 221000 Patentee before: Li Gui |