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Oxadiazole derivative having endothelial lipase inhibitory activity

A compound and solvate technology, applied in the field of oxadiazole derivatives with vascular endosebase inhibitory activity, can solve the problems of record of HDLc elevation without EL inhibitory effect and the like

Inactive Publication Date: 2012-10-24
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, Patent Document 16 does not describe EL inhibitory action or HDLc raising action

Method used

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  • Oxadiazole derivative having endothelial lipase inhibitory activity
  • Oxadiazole derivative having endothelial lipase inhibitory activity
  • Oxadiazole derivative having endothelial lipase inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0545] [chemical 40]

[0546]

[0547] To a solution of 2 M NaHMDS in THF (111 mL, 211 mmol) in 375 mL of anhydrous toluene was added ethyl acetate (11.30 mL, 116 mmol) dropwise over 10 min at -60 °C under nitrogen flow. Then it was stirred at -60°C for 1 hour, and then a solution of 6-bromo-2-chlorobenzothiazole 1 (25 g, 101 mmol) in 125 mL of anhydrous toluene was added dropwise. After completion of the dropwise addition, the mixture was stirred at 0° C. for 2 hours.

[0548] 1 M hydrochloric acid and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with a mixed solvent of hexane and diisopropyl ether to obtain Compound 2 (27.1 g, 90%) as a yellow solid.

[0549] Compound 2: 1H-NMR (CDCl3) δ: 1.31 (t, J = 7.2, 3.0Hz, 3H), 4.15 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 7.57 (dd, J = 8.7, 1.8Hz,...

Embodiment 2

[0551] [chem 41]

[0552]

[0553] At room temperature, tetrakis(triphenylphosphine)palladium(0) (5.39 g, 4.66 mmol), phenyl Boric acid (9.75 g, 80 mmol), K 3 PO 4 (35.4 g, 167 mmol), heated to reflux for 6 hours. The reaction was returned to room temperature, 1 M hydrochloric acid and ethyl acetate were added for extraction, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain Compound 3 (16.1 g, 81%) as a yellow solid.

[0554] Compound 3: 1 H-NMR (CDCl3) δ: 1.31(t, J = 6.9 Hz, 3H), 4.19 (s, 2H), 4.27 (q, J =7.2 Hz, 2H), 7.38 (t, J = 7.5Hz, 1H) , 7.48 (t, J = 7.2Hz, 2H), 7.63-7.73 (m, 3H), 8.06 (m, 2H).

[0555] Hydrazine hydrate (7.99 mL, 165 mmol) was added to a solution of compound 3 (9.8 g, 33 mmol) in 100 mL of anhydrous N-methylpyrrolidone, and stirred at 95°C for 7 hours. After returning the reaction...

Embodiment 3

[0566] [chem 42]

[0567]

[0568] To a solution of compound 4 (600 mg, 2.2 mmol) in 45 ml of anhydrous dimethylformamide was added successively 2-(tert-butoxycarbonylamino)acetic acid (464 mg, 2.65 mmol) at room temperature under a stream of nitrogen , WSCD HCl (609 mg, 3.18 mmol) and HOBt (86 mg, 0.635 mmol), stirred for 4 hours. 1 M hydrochloric acid and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over sodium sulfate. Ethyl acetate and hexane were added to the residue, and the precipitated insoluble matter was collected by filtration to obtain compound 6 (640 mg, 69%).

[0569] Compound 6: 1H-NMR (DMSO-d6) δ: 1.42 (s, 9H), 3.59 (d, J = 6.4Hz, 2H), 4.11 (s, 2H), 7.01 (br-s, 1H), 7.39 ( t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.8 Hz, 1H), 8.38(s, 1H), 10.19 (br s, 1H).

[0570] Burgess reagent (730 mg, 3.1 mmol) was added to a solution of compound...

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PUM

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Abstract

Provided is a compound useful as an endothelial lipase inhibitor. The compound is a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of either. In formula (I), ring A is an aromatic carbocycle or an aromatic heterocycle; Z is -NR5-, -O-, or -S-; R5 is a hydrogen atom, an (un)substituted alkyl, an (un)substituted aryl, etc.; R1 is a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, carboxy, an (un)substituted alkyl, etc.; R2 and R3 each independently is a hydrogen atom, a halogen atom, hydroxy, etc.; R4 is a group represented by the formula -(CR6R7)n-R8 (wherein R6 and R7 each independently is a hydrogen atom, a halogen atom, hydroxy, etc., n is an integer of 0-3, and R8 is carboxy, cyano, an (un)substituted alkyl, etc.); RX is a halogen atom, hydroxy, cyano, nitro, carboxy, an (un)substituted alkyl, etc.; and m is an integer of 0-3.

Description

technical field [0001] The present invention relates to a compound having vascular endothelial lipase (Endthelial Lipase, hereinafter referred to as EL) inhibitory activity and usable as a medicine. Background technique [0002] Endthelial Lipase (EL) is a triglyceride lipase (Triglyceride Lipase) family that is juxtaposed with lipoprotein lipase (Lipoprotein Lipase) (LPL) and liver lipase (Hepatic Lipase) (HL). Analysis of exogenous mice or transgenic mice revealed that they are involved in the metabolism of HDLc through strong phospholipase activity, and have attracted attention as a factor limiting the amount of HDLc in blood (Non-Patent Document 1). [0003] Previously known coronary artery disease (CAD) has a negative correlation with the amount of HDLc in the blood. HDLc shows anti-arteriosclerosis effects through anti-oxidation, anti-inflammation, reverse cholesterol transport, etc. Low HDLc is considered to be one of the risk factors for CAD. [0004] Therefore, EL...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06A61K31/4245A61K31/428A61K31/433A61K31/437A61K31/4439A61K31/454A61K31/5377A61P3/04A61P3/06A61P3/10A61P9/10A61P43/00C07D417/06C07D417/14C07D513/04
CPCA61K31/454A61K31/437C07D513/04A61K31/423C07D417/06A61K31/433A61K31/4245A61K31/4439A61K31/428A61K31/5377C07D417/14C07D413/06A61P3/00A61P3/04A61P3/06A61P3/10A61P9/10A61P43/00
Inventor 增田功嗣木田士郎吉川直树加藤学加藤辉和中岛麻童儿岛荣一米原光扩
Owner SHIONOGI & CO LTD
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