Sinomenine derivatives and their preparation methods and applications

A technology of sinomenine and its derivatives, which is applied in the field of macromolecular drug molecules, can solve problems such as structurally modified compounds not having ideal effects, and the mechanism of sinomenine is not completely clear, and achieve a wide range of applications, good curative effect, and high yield Effect

Inactive Publication Date: 2011-11-30
NANJING UNIV
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  • Abstract
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Problems solved by technology

However, so far, the mechanism of sinomenine used to treat inflammatory diseases is not comp...

Method used

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  • Sinomenine derivatives and their preparation methods and applications
  • Sinomenine derivatives and their preparation methods and applications
  • Sinomenine derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0032] Example 14, 4'-Diethylene glycol-bisinomenine (compound 2).

[0033] The reaction formula of preparing 4,4'-diethylene glycol-bisinomenine is:

[0034]

[0035] According to the above reaction formula, compound 1 (329g, 1mmol) and diethylene glycol bis-p-toluenesulfonic acid (207mg, 0.5mmol) were dissolved in tetrahydrofuran (15mL), and then added acid-binding agent sodium hydroxide (60mg, 1.5mmol ). After reflux reaction 16h, thin-layer chromatography detects that reaction is complete, then removes reaction solvent with rotary evaporator, and gained oily matter is purified with silica gel column (eluent CH 2 Cl 2 / CH 3 OH / NH 4 OH, 100:9:1, v / v / v), the corresponding compound 2 was obtained with a yield of 63%.

[0036] Compound 2 was characterized, and the specific results were: 1 H NMR (300MHz, CDCl 3 )δ6.71(d, J=8.4Hz, 2H), 6.67(d, J=8.4Hz, 2H), 5.44(d, J=1.5Hz, 2H), 4.15-4.38(m, 6H), 3.97( t, J=4.8Hz, 4H), 3.75(s, 6H), 3.46(s, 6H), 3.16(t, J=4.2Hz, 2H), 2....

Embodiment 24

[0037] Example 24, 4'-ethylene glycol-bisinomenine (compound 3).

[0038] The reaction formula of preparing 4,4'-triethylene glycol-bisinomenine is:

[0039]

[0040] As in the above reaction formula, compound 3 was obtained by the preparation method of Example 1, and compound 3 was characterized, and the specific results were: 1 H NMR (300MHz, CDCl 3 )δ6.70(d, J=8.7Hz, 2H), 6.66(d, J=8.7Hz, 2H), 5.44(d, J=1.2Hz, 2H), 4.17-4.32(m, 6H), 3.77- 3.93(m, 8H), 3.74(s, 6H), 3.36(s, 6H), 3.17(br t, J=4.2Hz, 2H), 2.94-2.98(br, 2H), 2.73(dd, J=18.6 , 5.1Hz, 2H), 2.44-2.53(m, 4H), 2.40(s, 3H), 1.96-2.03(m, 4H), 1.86(td, J=12.9, 3.6Hz, 2H); 13 C NMR (75MHz, CDCl 3 )δ193.8, 152.4, 151.3, 147.6, 129.8, 129.7, 122.6, 115.0, 111.3, 70.9, 70.7, 70.5, 56.4, 55.6, 54.7, 49.6, 47.0, 45.7, 42.4, 40.7, 36.6, 24.5. MS m / z: 773 (M+H) + .

Embodiment 34

[0041] Example 34, 4'-tetraethylene glycol-bisinomenine (compound 4).

[0042] The reaction formula of preparing 4,4'-tetraethylene glycol-bisinomenine is:

[0043]

[0044] As in the above reaction formula, compound 4 was obtained by the preparation method of Example 1, and compound 4 was characterized, and the specific results were: 1 H NMR (300MHz, CDCl 3 )δ6.72(d, J=8.4Hz, 2H), 6.67(d, J=8.4Hz, 2H), 5.46(d, J=1.8Hz, 2H), 4.16-4.33(m, 6H), 3.67- 3.80(m, 12H), 3.75(s, overlapped, 6H), 3.47(s, 6H), 3.15(t, J=3.9Hz, 2H), 2.95-3.00(m, 4H), 2.72(dd, J= 18.3, 5.4Hz, 2H), 2.43-2.52(m, 4H), 2.41(s, 6H), 1.94-2.03(m, 6H), 1.85(td, J=13.2, 4.2, 2H); 13 C NMR (75MHz, CDCl 3 )δ 193.9, 152.3, 151.2, 147.4, 130.0, 129.9, 122.6, 115.3, 111.2, 70.8, 70.6, 70.5, 70.4, 56.3, 55.6, 54.6, 49.6, 46.9, 45.9, 42.5, 40.8, 36.8, 24.4 ESI-MS m / z: 817(M+H) + .

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Abstract

The invention discloses sinomenine derivatives, and a preparation method and application thereof. The sinomenine derivatives are sinomenine derivative monomers or dimers formed by connecting the 4-position or 6-position carbon (C) of the frameworks of sinomenine and the conventional sinomenine derivatives with linker through X, wherein X is an ether bond, an ester bond, an amido bond, a sulfamide bond, or an amine bond and the like, and the linker is an aliphatic compound, an aromatic compound or polyethylene glycol and the like. The method for preparing the sinomenine derivatives is novel and unique, and simple and practicable; the prepared sinomenine derivatives have high purity and yield; when macrophages RAW264.7 in vitro are adopted to evaluate the NO inhibiting activity and anti-inflammatory action in rats, the sinomenine derivatives have high bioactivity, can be applied to preparing anti-inflammatory medicines for rheumatoid arthritis, rheumatic arthritis and the like, immunosuppressive agents and health products, have wide application range and good treatment effect, and have good social benefit.

Description

technical field [0001] The invention belongs to the technical field of macromolecular drug molecules and relates to sinomenine, in particular to a sinomenine derivative and its preparation method and application. Background technique [0002] Sinomenine (Sinomenine) is a morphine alkaloid extracted from the rhizomes of S. chinensis and S. tomentosa. Its hydrochloride has been widely used clinically to treat diseases such as rheumatic pain, rheumatoid arthritis and joint swelling. In addition, sinomenine also has drug activities such as analgesia, antihypertensive, anti-cancer and anti-cerebral ischemia, and other drug activities need to be further studied and discussed. At present, there are Zhengqing Fengtongning Tablets, Sinomenine total alkaloids, hydrochloride injection and other clinical drugs. However, due to the shortcomings of sinomenine itself, such as large doses and weak efficacy, the structure of sinomenine is modified in order to obtain a novel structure, Deri...

Claims

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Application Information

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IPC IPC(8): C07D221/28A61K31/485A61P29/00A61P19/02A61P37/06A23L1/30
Inventor 李建新滕鹏
Owner NANJING UNIV
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