Image may be NSFW.
Clik here to view.
MF | C 1 4 H 1 2 BrNO 2 S |
---|---|
MW | 338.21958 g / mol |
1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid
CAS…….1638327-48-6
Cyclobutanecarboxylic acid, 1-[(6-bromo-4-quinolinyl)thio]-
COMING ………….
Image may be NSFW.
Clik here to view.
MS m / z (ESI): 338.0 [M + l]
1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)
WO-2014183555-A1 / 2014-11-20
http://www.google.co.in/patents/WO2014183555A1?cl=en
PROCEDURE
6-bromo-quinoline-4-thiol
A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, using known methods “Bioorganic &
Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.
The second step
L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl carboxylate
Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were sequentially added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction solution was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.
MS m / z (ESI): 368.2 [M + l]
1H MR (400 MHz, CDCl 3 ) [delta] 8.67 (d, = 4.77 Hz, IH), 8.31 (d, = 2.13 Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H)
third step
L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid
L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the resulting A by thin layer chromatography in a developing solvent system, and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%.
MS m / z (ESI): 338.0 [M + l]
1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)
L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid
First step
6-bromo-quinoline-4-thiol
A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, a known method of “Bioorganic &
Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.
The second step
L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl
Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.
MS m / z (ESI): 368.2 [M + l]
1H MR (400 MHz, CDC1 3) δ 8.67 (d, = 4.77Hz, IH), 8.31 (d, = 2.13Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H) Step
L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid
L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to the resulting thin layer chromatography using a developing solvent system A and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%. MS m / z (ESI): 338.0 [M + l]
1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)
Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model
- Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China
This Letter describes the Discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURATl). Lead generation via 3D pharmacophore Analysis and Optimization resulted in compound 41 . With an IC 50 of 33.7 nM, 41 Also Demonstrated good Oral Bioavailability in RAT (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).
http://www.sciencedirect.com/science/article/pii/S0960894X1530353X
Volume 26, Issue 2 , 15 January 2016, Pages 277-282
Image may be NSFW.
Clik here to view.
Image may be NSFW.
Clik here to view.
//////// Shanghai Hengrui, inhibitors of Human Uric Acid Transporter 1 (hURAT1), 1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid
c13cc (ccc3nccc1SC2 (C (= O) O) CCC2) Br
Filed under: Preclinical china, Preclinical drugs Tagged: 1-(6-bromoquinolin-4-yl)sulfanylcyclobutane-1-carboxylic acid, inhibitors of Human Uric Acid Transporter 1 (hURAT1), preclinical, Shanghai Hengrui Image may be NSFW.
Clik here to view.
Clik here to view.
Clik here to view.
Clik here to view.
Clik here to view.
Clik here to view.
Clik here to view.
Clik here to view.
