CN104262276A - Benzene halide containing 1H-tetrazole-1-acetic acid compound, as well as preparation method and application thereof - Google Patents

Benzene halide containing 1H-tetrazole-1-acetic acid compound, as well as preparation method and application thereof Download PDF

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CN104262276A
CN104262276A CN201410525270.4A CN201410525270A CN104262276A CN 104262276 A CN104262276 A CN 104262276A CN 201410525270 A CN201410525270 A CN 201410525270A CN 104262276 A CN104262276 A CN 104262276A
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compound
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tetrazole
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CN104262276B (en
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Fu Yao
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04Five-membered rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a benzene halide containing 1H-tetrazole-1-acetic acid compound, a preparation method and application thereof, and relates to the field of drugs relative to hyperuricemia and gout, in particular to a series of urate transporter 1 inhibitors with a benzene halide containing 1H-tetrazole-1-acetic acid structure, a preparation method of the urate transporter 1 inhibitors, and a medicinal composition containing the urate transporter 1 inhibitors as well as application of the urate transporter 1 inhibitors in preparation of diabetes drugs. The formula is as shown in the formula (in the Specification), wherein X is selected from a halogen substituent.

Description

Containing tetrazoleacetic acid compounds, the Preparation Method And The Use of halogeno-benzene
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 the tetrazoleacetic acid structure of halogeno-benzene, 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 the tetrazoleacetic acid structure of halogeno-benzene, 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 compound that the present invention has general formula (I) has following structural formula:
Wherein, X is selected from halogenic substituent.
Preferred following general formula (I) compound,
Further, preferred following general formula (I) compound,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per reacts in the presence of a base with 4-halo butyronitrile III, obtains compound IV; Compound IV in the presence of a base with phenyl-dihalide C 6h 4x 2(V) compound VI is obtained by reacting; Compound VI and NaN 3at NH 4there is lower reaction in Cl, obtains product VII; VII and compound 2-halogenated acetic acids VIII is obtained by reacting product I in the presence of a base; X is selected from Cl, Br and I, and described alkali is selected from organic bases, mineral alkali, and X definition is corresponding as described in claim 1-3.
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
3.66g (20mmol) Compound II per-1 and 2.96g (20mmol) compound III-1 are dissolved in the DMF of 40mL drying, stir, add 3.32g (20mmol) potassiumiodide and 6.91g (50mmol) salt of wormwood, react at 100 DEG C in nitrogen atmosphere, until reacted (TLC follows the tracks of, general 5h).After reaction mixture cooling, pour in 300mL frozen water, stir, use 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=289 ([M+Na] +).
B. the synthesis of compound VI-1
Between 3.19g (12mmol) compound IV-1 and 1.76g (12mmol), toluene dichloride V-1 is dissolved in the DMF of 30mL drying, stir, add 4.98g (36mmol) salt of wormwood, react at 100 DEG C in nitrogen atmosphere, until reacted.After reaction mixture cooling, pour in 300mL frozen water, stir, use 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 VI-1, white solid, ESI-MS, m/z=399 ([M+Na] +).
C. the synthesis of compound VI I-1
3.01g (8mmol) compound VI-1 is dissolved in the DMF of 20mL drying, stirs, adds 1.30g (20mmol) NaN 3with 1.07g (20mmol) ammonium chloride, then react at 120 DEG C in nitrogen atmosphere, until reacted.After reaction mixture cooling, pour in 200mL frozen water, stir, use 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 VI I-1, white solid, ESI-MS, m/z=442 ([M+Na] +).
D. the synthesis of Compound I-1
2.09g (5mmol) compound VI I-1 and 1.39g (10mmol) bromoacetic acid is dissolved in 15mL ethanol, stirred at ambient temperature, slowly drip the 3mL aqueous solution containing 1.20g (30mmol) NaOH, gained mixture is warming up to 50 DEG C of heating, until reacted.After reaction mixture cooling, pour in 100mL frozen water, stir, concentrated hydrochloric acid regulates pH=2-3, uses the CH of 50mL × 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=476 ([M-H] -).
Embodiment 2-11
With reference to embodiment 1 operation steps, prepare compound listed in Table.
Embodiment 12
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)
Embodiment 1 compound 5.2
Embodiment 2 compound 14.3
Embodiment 3 compound 7.7
Embodiment 4 compound 10.6
Embodiment 5 compound 11.9
Embodiment 6 compound 15.5
Embodiment 7 compound 14.9
Embodiment 8 compound 17.8
Embodiment 9 compound 11.4
Embodiment 10 compound 9.4
Embodiment 11 compound 13.7
Above-mentioned IC 50measurement result show, compound of the present invention is strong URAT1 inhibitor, can be used for preparing treatment hyperuricemia and the medicine of gout.

Claims (5)

1. there is the compound of general formula I,
Wherein, X is selected from halogenic substituent.
2. the compound of Formula I that defines of claim 1, is selected from:
3. the compound of Formula I that defines of claim 2, is selected from:
4. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-3:
Compound II per reacts in the presence of a base with 4-halo butyronitrile III, obtains compound IV; Compound IV in the presence of a base with phenyl-dihalide C 6h 4x 2(V) compound VI is obtained by reacting; Compound VI and NaN 3at NH 4there is lower reaction in Cl, obtains product VII; VII and compound 2-halogenated acetic acids VIII is obtained by reacting product I in the presence of a base; Described alkali is selected from organic bases, mineral alkali, and X definition is corresponding as described in claim 1-3.
5. the compound of Formula I that one of claim 1-3 defines is preparing the application in treatment hyperuricemia and gout medicine.
CN201410525270.4A 2014-10-07 2014-10-07 Tetrazoleacetic acid compounds containing halogeno-benzene, Preparation Method And The Use Active CN104262276B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032377A (en) * 2015-03-12 2016-10-19 天津药物研究院有限公司 Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356977A (en) * 1999-05-17 2002-07-03 诺沃挪第克公司 Glucagon antagonists/inverse agonists
WO2008021804A2 (en) * 2006-08-09 2008-02-21 Allergan, Inc. Therapeutic amides and related compounds
WO2008062740A1 (en) * 2006-11-20 2008-05-29 Japan Tobacco Inc. Nitrogenated fused ring compound and use thereof
EP1985297A1 (en) * 2006-01-27 2008-10-29 Japan Tobacco, Inc. Carboxylic acid compound and use thereof
US20100056542A1 (en) * 2008-09-04 2010-03-04 Ardea Biosciences Compounds, compositions and methods of using same for modulating uric acid levels
WO2010135530A2 (en) * 2009-05-20 2010-11-25 Ardea Biosciences, Inc. Compounds, compositions and methods for modulating uric acid levels

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356977A (en) * 1999-05-17 2002-07-03 诺沃挪第克公司 Glucagon antagonists/inverse agonists
EP1985297A1 (en) * 2006-01-27 2008-10-29 Japan Tobacco, Inc. Carboxylic acid compound and use thereof
WO2008021804A2 (en) * 2006-08-09 2008-02-21 Allergan, Inc. Therapeutic amides and related compounds
WO2008062740A1 (en) * 2006-11-20 2008-05-29 Japan Tobacco Inc. Nitrogenated fused ring compound and use thereof
US20100056542A1 (en) * 2008-09-04 2010-03-04 Ardea Biosciences Compounds, compositions and methods of using same for modulating uric acid levels
WO2010135530A2 (en) * 2009-05-20 2010-11-25 Ardea Biosciences, Inc. Compounds, compositions and methods for modulating uric acid levels

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032377A (en) * 2015-03-12 2016-10-19 天津药物研究院有限公司 Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout

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Address after: 226400 No. 64 fan Dian Road, dugong Town, Rudong County, Nantong, Jiangsu

Patentee after: Fu Yao

Address before: 528000 floor 5, Pu Lan Road, Chancheng District, Foshan, Guangdong.

Patentee before: Zhang Yuanqiang