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.

CN108929263AActive Publication Date: 2018-12-04INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
6 Cites 0 Cited by

Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
Publication Date
2018-12-04

Smart Images

  • Figure 1
    Figure 1
  • Figure 2
    Figure 2
  • Figure 3
    Figure 3
Patent Text Reader

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.
Need to check novelty before this filing date? Find Prior Art

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...

Examples

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=...