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Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof

A technology for compounds and medicinal salts, which can be applied in the fields of drug combination, preparation of carboxylic acid amides, active ingredients of amides, etc., can solve the problems of poor selectivity, limited application, limited sources of polypeptides, etc.

Active Publication Date: 2018-12-04
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The early discovered Kv2.1 selective blockers are some polypeptide compounds, which come from the venoms of spiders, toads and other animals, such as: Jingzhao toxin-I, Jingzhao toxin-III and GxTX- 1E, etc., but the limited sources of these peptides limit their use in pharmacology
Most of the Kv2.1 small-molecule blockers reported in the literature are found through the general screening method, with weak inhibitory activity and poor selectivity, such as: SC-791 [Brain research, 2010, 1359:67-74], propafenone [ Naunyn-Schmiedeberg's archives of pharmacology, 2000, 362 (1): 22-31], trifluperidol [Brain research, 1997, 761 (1): 42-50], 17β-estradiol [Acta Pharm Sin (Pharmaceutical Acta Sinica), 2004,39(9):686-690], Bugfuran (AF-5)[Acta Pharm Sin (Acta Pharmaceutica), 2013,48(1):38-44], etc.

Method used

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  • Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof
  • Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof
  • Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0411] Preparation of intermediates

[0412] (1) 2-(dimethylamino)-5-nitrobenzoic acid

[0413]

[0414] Take 2-chloro-5-nitrobenzoic acid (2.0g, 10.00mmol), add dimethylamine (40% aqueous solution) (20mL), heat to 65°C, after 8h the reaction of raw materials is complete, add dilute acetic acid solution dropwise, Adjust the pH to acidic, extract with EA (30mL×5), combine and concentrate, and dry to obtain 1.6g of yellow solid, 76.7%.

[0415] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 8.92 (d, J = 2.8Hz, 1H), 8.33 (dd, J = 9.2, 2.8Hz, 1H), 7.36 (d, J = 9.2Hz, 1H), 2.96 (s, 6H) ;ESI-MS m / z:209.06[M-H] - .

[0416] (2) Preparation of 2-ethoxy-5-benzoic acid

[0417]

[0418] a) Methyl 2-hydroxy-5-nitrobenzoate

[0419]

[0420] 2-Hydroxy-5-nitrobenzoic acid (6 g, 32.7 mmol) was dissolved in anhydrous methanol (50 mL), and SOCl was added slowly under stirring 2 The solution was reacted at 60°C for 10 h, cooled, filtered, and the filter cake was washed with ice methanol to...

Embodiment 1

[0493] 2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-2-ylmethyl)benzamide

[0494]

[0495] a) 2-(dimethylamino)-5-nitro-N-(pyridin-2-ylmethyl)benzamide

[0496] Dissolve 2-(dimethylamino)-5-nitrobenzoic acid (200mg, 0.95mmol) in DMF (15mL), add DIEA (185mg, 1.43mmol) and HATU (542mg, 1.43mmol) successively, and add after 20min 2-Aminomethylpyridine (93mg, 0.86mmol), stirred overnight at room temperature. Concentrate, add EA (20mL) to dilute, wash with HCl (0.5N) (10mL), saturate with NaHCO 3 (10mL) wash, water (10mL) wash, anhydrous Na 2 SO 4 It was dried and purified by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 248 mg of yellow solid, yield 95.0%, melting point: 140-142°C.

[0497] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 8.58-8.55 (m, 2H), 8.27 (s, 1H), 8.17 (dd, J = 9.2, 1.6Hz, 1H), 7.71 (t, J = 7.6Hz, 1H), 7.36 ( d,J=7.6Hz,1H),7.23(d,J=6.0Hz,1H),6.96(d,J=9.2Hz,1H),4.78(d,J=4.8Hz,2H),2.95(s, 6H); HR-MS (ESI): m / z, calcd. For C ...

Embodiment 2

[0502] 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(pyridin-2-yl)ethyl)benzamide

[0503]

[0504] a) 2-(Dimethylamino)-5-nitro-N-(1-(pyridin-2-yl)ethyl)benzamide

[0505] Dissolve 2-(dimethylamino)-5-nitrobenzoic acid (356mg, 1.69mmol) in DMF (10mL), add DIEA (696mg, 5.40mmol) and HATU (965mg, 2.54mmol) successively, and stir for 20min Then 1-(pyridin-2-yl)ethylamine·hydrochloride (300mg, 1.54mmol) was added and stirred overnight at room temperature. Concentrate, add EA (20mL) to dilute, wash with saturated ammonium chloride solution (10mL), wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, anhydrous Na 2 SO 4 It was dried and purified by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 247 mg of yellow solid, yield 51.1%, melting point: 158-160°C.

[0506] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 8.56 (d, J = 4.8Hz, 1H), 8.49 (d, J = 2.8Hz, 1H), 8.35 (d, J = 6.8Hz, 1H), 8.14 (dd, J = 9.2, 2.8Hz, 1H), 7.73(t, J=7.6Hz, 1H), 7.35(d, J=...

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Abstract

The present invention provides a novel aromatic amide as a Kv2.1 inhibitor and a preparation method, pharmaceutical composition, and use thereof. In particular, the present invention relates to an aromatic amide derivative shown in general formula I and a pharmaceutically acceptable salt thereof, a preparation method of the same, a composition comprising one or more such compounds, and a use of such compounds in preparing a drug for preventing and / or treating a disease related to Kv2.1.

Description

technical field [0001] The present invention relates to an aromatic amide Kv2.1 inhibitor with a new structure shown in formula I, its pharmaceutically acceptable salt, and a preparation method thereof, a composition containing one or more of such compounds, and such compounds in inhibiting Kv2 .1 Diseases related to the treatment of kv2.1, and its use in the preparation, prevention and / or treatment of drugs for mental and nervous system diseases, metabolic diseases and cardiovascular and cerebrovascular diseases. Background technique [0002] Voltage-gated potassium channels (Kv channels) widely exist on the surface of many excitable cell membranes, and can participate in the regulation of cell electrophysiological activities and endocrine. For example, in excitatory cells, Kv channels can regulate the depolarization of action potentials, and in non-excitatory cells, it can regulate the resting potential of cell membranes, so Kv channels can participate in many electrophysi...

Claims

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Application Information

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IPC IPC(8): C07D213/40C07C237/40C07D307/52C07D307/14C07D277/28C07D211/16C07D207/04C07D417/12C07C237/44C07D211/76C07D207/27C07D295/135C07D295/182C07D261/04C07D277/56C07D237/08C07D231/12C07D233/61C07D205/04C07D213/64C07D213/73C07D213/61C07D239/42C07D241/12C07D239/26C07D333/20C07D277/40C07D317/58C07D277/82C07D235/30C07D235/08C07D213/82C07D213/81A61P3/00A61P3/10A61P9/00A61P25/00A61P25/24A61P25/28A61P9/10A61K31/166A61K31/18A61K31/192A61K31/235A61K31/341A61K31/36A61K31/381A61K31/397A61K31/40A61K31/4015A61K31/415A61K31/4164A61K31/4184A61K31/421A61K31/426A61K31/427A61K31/4523A61K31/4462A61K31/4465A61K31/495A61K31/50A61K31/501A61K31/505
CPCA61P3/00A61P3/10A61P9/00A61P9/10A61P25/00A61P25/24A61P25/28C07C237/40C07C237/44C07D205/04C07D207/04C07D207/27C07D211/16C07D211/76C07D213/40C07D213/61C07D213/64C07D213/73C07D213/81C07D213/82C07D231/12C07D233/61C07D235/08C07D235/30C07D237/08C07D239/26C07D239/42C07D241/12C07D261/04C07D277/28C07D277/40C07D277/56C07D277/82C07D295/135C07D295/182C07D307/14C07D307/52C07D317/58C07D333/20C07D417/12C07C2601/02A61K31/166A61K31/167A61K31/18A61K31/192A61K31/235A61K31/341A61K31/36A61K31/381A61K31/397A61K31/40A61K31/4015A61K31/415A61K31/4164A61K31/4184A61K31/421A61K31/426A61K31/427A61K31/4462A61K31/4465A61K31/4523A61K31/495A61K31/50A61K31/501A61K31/505C07C231/02C07C235/46
Inventor 徐柏玲王晓良周洁王伟平刘冬郭婷婷王雪冯楠陈华龙徐少峰李江王玲
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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