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Nitrogen-containing substituent curcumin analogue and medical application thereof

A technology based on curcumin and nitrogen substitution, which is applied in the field of anti-tumor and neurodegenerative diseases, can solve the problems of non-absorption of curcumin after oral administration, limited medicinal development prospects, low bioavailability, etc., and achieves easy penetration through the blood-brain barrier. , mild inhibitory effect, efficient scavenging effect

Active Publication Date: 2012-09-19
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, further in vivo pharmacodynamic and pharmacokinetic studies have found that curcumin has disadvantages such as non-absorption, poor targeting, and low bioavailability after oral administration, which greatly limits its medicinal development prospects.

Method used

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  • Nitrogen-containing substituent curcumin analogue and medical application thereof
  • Nitrogen-containing substituent curcumin analogue and medical application thereof
  • Nitrogen-containing substituent curcumin analogue and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1.3-dimethylaminomethyl-4-hydroxybenzaldehyde (compound 2a ) preparation

[0034]

[0035] 1.00 g (8 mmol) 4-hydroxybenzaldehyde, 1.12 g (8 mmol) dimethylamine in water (33%), 0.80 g (9.8 mmol) formaldehyde in water (37%) in 20 mL of methanol at 50 °C React overnight. The methanol was distilled off under reduced pressure, the residue was extracted with ethyl acetate (15 mL×3), the organic phases were combined, and washed with anhydrous Na 2 SO 4 Drying, concentration, and column chromatography using ethyl acetate / petroleum ether mixture as eluent gave 0.57 g of a light yellow oil, which solidified into a solid after standing. The yield was 39%, m.p.80~81°C. 1 H NMR (CDCl 3, 500MHz): δ 9.81 (s, 1H, C H O), 8.61 (s, 1H, O H ), 7.71-7.69 (m, 1H, aroma), 7.55-7.54 (d, 1H, aroma), 6.92-6.90 (d, 1H, aroma), 3.73 (s, 1H, C H 2 ), 2.36 (s, 6H, N(C H 3 ) 2 ); IR (KBr): v 3421.4 (O-H), 2957.6, 2863.6 (C-H, CH 3 ), 2729.5 (C-H, CHO), 1684.2 (C=O), 159...

Embodiment 2

[0036] Embodiment 2.5-hydroxyl-1-(3-dimethylaminomethyl-4-hydroxyl)-1,4-pentadien-3-one ( 3a ) preparation

[0037]

[0038] 0.79 g (7.92 mmol) acetylacetone and 0.50 g (7.18 mmol) B 2 o 3 Dissolve in ethyl acetate (5 mL), stir at 80°C for 30 min; add 0.65 g (3.6 mmol) of 2a and 0.34 g (1.48 mmol) (n-BuO) 3 B, continue to stir at 80°C for 30min; then add 0.10 g (1.43 mmol) of n-butylamine dropwise, stir at 100°C for 2h; then cool to 50°C, add 1N HCl aqueous solution (10mL), and stir for 30min. Cooled to room temperature, the reaction solution was extracted with ethyl acetate (25 mL×3), the organic phase was washed with saturated NaCl (15 mL×2), anhydrous NaCl 2 SO 4 After drying, column chromatography using ethyl acetate / petroleum ether mixture as eluent gave 0.13 g of a yellow solid with a yield of 14%, m.p.105-106°C. 1 HNMR (CDCl 3 , 500MHz): δ 15.53 (s, 1H, CH=C-O H ), 7.53-7.50 (d, 1H, arom-C H =CH), 7.38-7.36 (m, 1H, aroma), 7.14-7.14 (d, 1H, aroma), 6.83-6....

Embodiment 3

[0039] Example 3. 1-(3-Dimethylaminomethyl-4-hydroxyphenyl)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1,4,6-pentanetri En-3-one ( 4a ) preparation

[0040]

[0041] 0.38 g (1.44 mmol) compound 3a and 0.15 g (2.13 mmol) B 2 o 3 Dissolve with ethyl acetate (5 mL). Add 4-hydroxy-3-methoxybenzaldehyde 0.30 g (2.00 mmol) and 0.49 g (2.11 mmol) (n-BuO) 3 5 mL ethyl acetate solution of B, stirred at 80°C for 30 min; added 0.04 g (0.51 mmol) n-butylamine, continued to stir at 80°C for 1 h; cooled to 50°C, added 0.4N HCl aqueous solution (5 mL), and stirred again 30min. Cooled to room temperature, the reaction solution was extracted with ethyl acetate (25 mL×3), washed with saturated NaCl (15 mL×3), anhydrous NaCl 2 SO 4 After drying, column chromatography using ethyl acetate / petroleum ether mixture as eluent gave 0.26 g of a yellow solid with a yield of 46%, m.p.158~160°C. 1 H NMR (CDCl 3 , 300Hz): δ 7.63-7.58 (d, 2H, CH=CH), 7.44-7.44 (m, 1H, aroma), 7.23-7.23 (d, 1H, a...

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Abstract

The invention discloses a nitrogen-containing substituent curcumin analogue and a medical application thereof. According to the nitrogen-containing substituent curcumin analogue and the medical application thereof, a substituent on an aromatic nucleus of curcumin is changed, one or more nitrogen-containing substituents are introduced to obtain a novel curcumin analogue and salt acceptable in the pharmaceutical field, a nitrogen-containing substituent group is introduced at positions of 3' and / or 3', the general formula of the structure is represented as formula (1), wherein R1 is an alkyl of C1-6, R2 is an alkyl of a hydrogen atom or C1-6, R3 is a hydrogen atom, a methyl or -CH2NX2, X is an alkyl of C1-6, and R4 is a hydroxyl, an alkoxy of C1-6, an alkyl of C1-6 or a halogen atom. Part of compounds show good in vitro anti-tumor activity and anti-neurodegenerative disease activity, are provided with better water solubility than curcumin, and can be applied to treatment of diseases such as tumors and neurodegenerative diseases.

Description

technical field [0001] The invention relates to a class of novel nitrogen-containing substituent curcumin analogs and pharmaceutically acceptable salts thereof and their application in anti-tumor and neurodegenerative diseases. Background technique [0002] Curcumin (Curcumin) is a kind of natural plant extract, and it mainly exists in the rhizome of Curcuma longa plant such as turmeric, turmeric, etc., and its content is relatively high, easy to extract, and cost is low. Curcumin has diverse biological activities. Studies have found that curcumin has good in vitro anti-tumor activity against many types of tumor cells. It can not only prevent / block carcinogen-induced carcinogenesis, but also directly induce tumor cell apoptosis and inhibit tumor growth. invasion and migration. Recent studies have also reported that curcumin can effectively inhibit amyloid (Aβ) aggregation, and has certain anti-inflammatory and antioxidant activities, so it has potential curative effect in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/16C07C221/00A61P35/00A61P39/06A61P25/00
Inventor 房雷苟少华房旭彬陈蕾
Owner SOUTHEAST UNIV
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