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Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same

A technology of fumagillol and derivatives, applied in drug combination, antitumor drugs, organic chemistry and other directions

Inactive Publication Date: 2008-03-12
CHONG KUN DONG CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the angiogenesis inhibitory effect of the above-mentioned fumagillol derivatives is very important, the problems of toxicity, chemical stability and solubility still need to be improved

Method used

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  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same
  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same
  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1: Preparation of O-(4-(2-hydroxyethoxy)cinnamoyl) fumagillol

[0092] Step 1: Preparation of O-(4-acetoxycinnamoyl) fumagillol

[0093] 4-acetoxycinnamic acid (1.825 g, 8.85 mmol) was stirred in toluene (20 ml), thionyl chloride (1.29 ml, 1.77 mmol) was added dropwise thereto, and the resulting mixture was stirred under reflux for 4 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dimethylformamide (20 ml). Sodium hydride (850 mg, 21.25 mmol) and the compound of Chemical Formula 2 (1.0 g, 3.54 mmol) were added dropwise thereto, and the resulting mixture was then stirred at normal temperature for 4 hours. This solution was added to a saturated aqueous ammonium acetate solution (200 ml), and then extracted with ethyl acetate (250 ml). The organic layer was washed 3 times with a saturated saline solution (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. T...

Embodiment 2

[0101] Example 2: Preparation of O-(3,5-dimethoxy-4-(2-hydroxyethoxy)cinnamoyl)fumagillol

[0102] Step 1: Preparation of O-(4-acetoxy-3,5-dimethoxycinnamoyl) fumagillol

[0103] Repeat the same method described in step 1 of Example 1, but using the compound of formula 2 (1.0g), 4-acetoxy-3,5-dimethoxycinnamic acid (2.36g), thionyl chloride (1.29 ml), toluene (20ml), sodium hydride (850mg) and dimethylformamide (20ml) to give 1.36g (72%) of the title compound as a white solid.

[0104] 1 H-NMR (400MHz, CDCl 3 )δ: 7.59 (d, 1H, J = 16Hz), 6.77 (s, 2H), 6.44 (d, 1H, J = 16Hz), 5.71 (m, 1H), 5.21 (m, 1H), 3.86 (s, 3H), 3.71 (dd, 1H, J = 11, 2.7 Hz), 3.45 (s, 3H), 3.0 (d, 1H, J = 4.0 Hz), 2.62 (t, 1H, J = 6.4 Hz), 2.57 ( d, 1H, J = 4.0 Hz), 2.36 (m, 1H), 2.34 (s, 3H), 2.20-2.04 (m, 4H), 1.89 (m, 1H), 1.74 (s, 3H), 1.65 (s , 3H), 1.23(s, 3H), 1.10(m, 1H).

[0105] Step 2: Preparation of O-(3,5-dimethoxy-4-hydroxycinnamoyl) fumagillol

[0106] Repeat the same method described in step 2 o...

Embodiment 3

[0111] Example 3: Preparation of O-(4-(2-hydroxyethoxy)-3-methoxycinnamoyl) fumagillol

[0112] Step 1: Preparation of O-(4-acetoxy-3-methoxycinnamoyl) fumagillol

[0113] Repeat the same method described in step 1 of Example 1, but using the compound of formula 2 (1.0g), 4-acetoxy-3-methoxycinnamic acid (2.09g), thionyl chloride (1.29ml), Toluene (20ml), triethylamine (2.7ml) and dichloromethane (20ml) gave 1.0g (56%) of the title compound as a bright yellow syrup.

[0114] 1 H-NMR (400MHz, CDCl 3 )δ: 7.62(d, 1H, J=16Hz), 7.13-7.03(m, 3H), 6.44(d, 1H, J=16Hz), 5.73(m, 1H), 5.43(m, 1H), 5.21( m, 1H), 3.88 (s, 3H), 3.71 (dd, 1H, J = 11.2, 2.8 Hz), 3.45 (s, 3H), 3.00 (d, 1H, J = 4 Hz), 2.62 (t, 1H, J=6.3Hz), 2.57(d, 1H, J=4Hz), 2.35(m, 1H), 2.32(s, 3H), 2.20-2.04(m, 4H), 1.89(m, 1H), 1.74(s , 3H), 1.65(s, 3H), 1.23(s, 3H), 1.11(m, 1H).

[0115] Step 2: Preparation of O-(4-hydroxy-3-methoxycinnamoyl) fumagillol

[0116] Repeat the same method described in step 2 of Example 1, but usi...

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Abstract

The present invention relates to a fumagillol derivative and the pharmaceutically acceptable salt thereof, and a method for preparing the compound. The compound of the invention can be prepared by acidylation, hydrolyzation and alkylation. The compound of the invention can be prepared to the form of pharmaceutically acceptable salt or inclusion compound. Comparing with the conventional angiogenesis inhibitor, the fumagillol derivative provided with the invention has more excellent angiogenesis inhibition function, low toxicity, excellent dissolvability and chemical stability. The compound of the invention can be used as anticancer medicine, cancerometastasis restrainer, or the remedy for treating the rheumatoid arthritis, psoriasis, diabetic retinopathy or adiposis.

Description

Technical field [0001] The present invention relates to a fumagillol derivative or a preparation method thereof, and a pharmaceutical composition containing the derivative. Background technique [0002] Angiogenesis is a phenomenon that produces new capillaries, which is one of the pathological phenomena that occur in various diseases, and it is also a normal physiological function. [0003] In addition, angiogenesis is deeply related to the growth and metastasis of solid tumors, rheumatoid arthritis, diabetic retinopathy, psoriasis, etc. [Billington, DCDrug Design and Discovery, (1991), 8, 3.], and inhibits blood vessels The resulting compound also has a therapeutic effect on obesity [J. Folkman, PNAS, (2002), 99, 10730-10735]. [0004] Compounds that inhibit angiogenesis have been developed and reported in many studies. Recently, as people have begun to emphasize the clinical importance of therapeutic agents that control angiogenesis, research on angiogenesis has increased. Spe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/08
CPCC07D303/28A61P17/06A61P19/02A61P27/02A61P3/04A61P35/00A61P35/04
Inventor 李相俊安舜吉李洪雨安重福申在洙权宁珉
Owner CHONG KUN DONG CORP
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