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Veratramine degradation product veratrum fluorene aldehyde and the derivatives thereof, as well as the preparation and application thereof

A degradation product, veratramine technology, applied in the direction of drug combinations, steroids, medical preparations containing active ingredients, etc., can solve the problem of high toxicity of compounds

Inactive Publication Date: 2013-03-13
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The steroidal alkaloid-veratramine (structure following formula A) that is isolated from Veratrum has significant antitumor activity, but the toxicity of this compound is larger, and mouse intravenous and subcutaneous administration, its LD 50 3.1 mg / kg and 4.5 mg / kg, respectively (Kiyoshi Tanaka, J. Pharma. Exp. Therapeutics. 1955, 113(1): 89-99)

Method used

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  • Veratramine degradation product veratrum fluorene aldehyde and the derivatives thereof, as well as the preparation and application thereof
  • Veratramine degradation product veratrum fluorene aldehyde and the derivatives thereof, as well as the preparation and application thereof
  • Veratramine degradation product veratrum fluorene aldehyde and the derivatives thereof, as well as the preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Dissolve 2.0g (4.9mmol) of veratramine A in 40mL of toluene, add 5mL of cyclohexanone (48.2mmol) and 2.0g (9.8mmol) of aluminum isopropoxide, raise the temperature to 110°C for 3h, distill off the toluene to obtain Yellow oil, purified by silica gel column to obtain white powder compound 3-carbonyl-Δ 4 - Veratramine B (1.2g), yield 60.3%, melting point 187-189°C.

[0026] 3-Carbonyl-Δ 4 -Structure Confirmation of Veratramine (B):

[0027] ESI-MS: m / z 408[M+H] + , 1 H-NMR (600MHz, CDCl 3 , J / Hz) δ: 7.24 (d, 1H, J=7.8, H-16), 6.98 (d, 1H, J=7.8, H-15), 5.83 (s, 1H, H-4), 3.50 ( dd, 1H, J=6.6, 4.8, H-20), 3.26(m, 1H, H-23), 3.06(m, 1H, H-8), 2.92(dd, 1H, J=12, 1.8, H -26 b ), 2.76(q, 1H, H-11 b ), 2.61(m, 1H, H-6 b ), 2.56(m, 1H, H-11 a ), 2.55(m, 1H, H-2 b ), 2.49(d, 1H, J=4.2, H-22), 2.47(m, 1H, H-6 a ), 2.43 (brs, 1H, H-7 b ), 2.40 (brs, 1H, H-2 a ), 2.32 (brs, 3H, H-18), 2.11 (t, 1H, J=11.4, H-26 a ), 2.04(m, 1H, H-1 b ), 2.02(m, 1H, H-24 b ), 1.90 (td...

Embodiment 2

[0029] 0.5g (1.2mmol) 3-carbonyl-Δ 4 - Dissolve veratramine (B) in 50mL diethylene glycol, add 1.0mL (20mmol) hydrazine hydrate, 1.2g (21mmol) potassium hydroxide, stir at 160°C, cool down to 120°C after 2h, remove The water in the system was heated up to 180°C and reacted for about 4 hours. The reaction solution was added to 150 mL of ice water, left to stand in the refrigerator for 2 h, and filtered to obtain 0.36 g of a white solid. Crystallize with 50 mL of acetone to obtain 0.20 g of white powder. The mother liquor is applied to a silica gel column and eluted with a gradient petroleum ether: ethyl acetate mixture to obtain 3-deoxy-Δ as a white solid 4 - Veratramine (C) 46mg, yield 52.2%, ESI-MS: m / z 394[M+H] + .

Embodiment 3

[0031] In a stirred 50mL autoclave, add 3-deoxy-Δ 4 - Veratramine (C) 0.3g, ethanol 20mL, Pd / C 50mg, replace the air in the reactor with hydrogen and pressurize to 350psi, react at room temperature for 6-8h, filter and recover Pd / C, evaporate the solvent to obtain a solid 0.3 g, put on a silica gel column, and eluted with a gradient petroleum ether: ethyl acetate mixture to obtain 256 mg of white solid 3-deoxy-5,6-dihydro-veratramine (D), with a yield of 85%, ESI -MS: m / z 396[M+H] + .

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Abstract

The invention provides a veratramine degradation product veratrum fluorene aldehyde 1 and derivatives thereof. The invention uses steroidal alkaloid veratramine (A) as raw material and prepares veratrum fluorene aldehyde by oxidative degradation of m-chloroperoxybenzoic acid to obtain 20 derivative compounds of the veratrum fluorene aldehyde 1 after further oxidation, reduction and condensation reaction. The 20 compounds of the invention have good inhibitory activity on cancer cells, wherein the compounds 1, 2, 5, 8, 13 and 17 have good inhibitory activity on cells of human pancreatic cancer cells BxPC-3 and SW1990, small-cell lung cancer cells NCI-H446, human colorectal cancer LOVO and the like, and the inhibitory activity of the compound veratrum fluorene aldehyde 1 is the most significant.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to veratramine degradation product veratryl fluorenal and its derivatives and their preparation and application in the preparation of antineoplastic drugs. Background technique [0002] Veratrum (Veratrum) is a plant of Liliaceae (Liliaceae), and there are about 40 species in the world. Veratrum for traditional Chinese medicine (V.nigrum L.), Xing'an veratrum (V.dahuricum (Turcz.) Loes.f.), Tianmu veratrum (V.SchindleriLoes.f.), hairy veratrum (V.maackii Regel), The roots and rhizomes of Veratrum Dali (V..taliense Loes.f.) and Veratrum (V.grandiflorum (Maxim.) Loes.f.) are used as medicine for stroke, phlegm congestion, epilepsy, sore throat obstruction, and scabies Ringworm and malignant sores (Chinese Materia Medica (VIII). Shanghai Science and Technology Press, 1999, 183-188). Modern pharmacological studies have shown that Veratrum alkaloids have hypotensive and antitumor effects (Ci Hai ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J69/00A61K31/56A61P35/00
Inventor 张卫东李慧粱汤建单磊苏娟柳润辉沈云亨徐希科
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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