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Antitumor compound and its prepn process

A compound and lower alkane technology, applied in the field of antitumor compounds and their preparation, can solve the problems of poor bioavailability, toxic and side effects, and difficulty in synthesis

Inactive Publication Date: 2007-08-22
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the application and preparation of these drugs have the following problems: as a natural product of a macromolecule, it is very difficult to synthesize, has poor bioavailability, and has toxic side effects. In particular, the multidrug-resistant glycoprotein (P -gp), the effectiveness of its treatment has been seriously challenged (Li, Jian-Nong; Song, Dan-Qing; Lin, Yi-He; et al.Biochemical Pharmacology (2003), 65 (10), 1691-1699), which to some extent limited the development and use of paclitaxel and vinblastine-based tubulin inhibitors

Method used

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  • Antitumor compound and its prepn process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: (N-9-ethylcarbazole-3-substituted)-(3,4,5-trimethoxyphenyl)-methanol (123)

[0094] Add 2.5ml of anhydrous THF, magnesium strips (0.24g, 10mmol) and a few materials of iodine into the reaction flask, warm with an oil bath, and add about 1 / 4 of the total amount of 1-bromo-3,4,5- Trimethoxybenzene (2.47 g in total, 10 mmol) was dissolved in 10 ml of anhydrous THF solution. When the solution became colorless, the remaining THF solution of 1-bromo-3,4,5-trimethoxybenzene was slowly added dropwise to keep the solution slightly boiling. After the addition was complete, stirring was continued at room temperature for 1 hour. Then, the prepared THF solution of 3,4,5-trimethoxybenzenemagnesium bromide was slowly added to another 2.5ml of 9-ethyl-3-carbazole aldehyde (1.86g, 8.35mmol) without Aqueous THF solution, continue to react for 1 hour. Slowly add saturated NH at 0°C 4 Cl solution, and after 10 min, the solution was separated. The aqueous phase was extracted...

Embodiment 2

[0098] Example 2: (N-9-ethylcarbazole-3-substituted)-(3,4,5-trimethoxyphenyl)-methanone (124)

[0099] Pyridinium dichromate (PDC, 1.69 g, 4.5 mmol) was added to 30 ml of anhydrous CH containing compound 123 (1.17 g, 3 mmol) and molecular sieves 0.45 g at 0 °C 2 Cl 2 solution. After the addition was complete, it was stirred overnight at room temperature. The reaction solution was diluted with 50ml of ether and filtered. The filtrate was concentrated and separated by VLC to obtain off-white solid (0.90 g, yield 77%), which was compound 124, mp 125-126°C.

[0100] 1 H NMR (DMSO-d 6 ); δ1.35(t, J=7.2Hz, 3H), 3.78(s, 3H), 3.81(s, 6H), 4.39(q, J=7.2Hz, 2H), 7.07(s, 2H), 7.25 (dd, J=7.2, 7.8Hz, 1H), 7.42(dd, J=7.2, 6.9Hz, 1H), 7.68(d, J=8.1Hz, 1H), 7.73(d, J=8.4Hz, 1H) , 7.94 (dd, J=8.7, 1.5Hz, 1H), 8.31 (d, J=7.8Hz, 1H), 8.66 (d, J=1.2Hz, 1H).

[0101] 13 C NMR (DMSO-d 6 );

[0102] Elemental Analysis: C 24 h 23 NO 4 . Calculated: C, 74.01; H, 5.96; N, 3.60. Found: ...

Embodiment 3

[0103] Example 3: (2,6-dimethoxypyridine-3-substituted)-(N-9-ethylcarbazole-3-substituted)-methanol (135)

[0104] The compound 135 was prepared from the corresponding 3-bromo-2,6-dimethoxypyridine and 9-ethyl-3-carbazole aldehyde in the same manner as in Example 1. The product is light yellow solid, yield: 80%.

[0105] 1 H NMR (DMSO-d 6 ); δ1.27(t, J=6.9Hz, 3H), 3.81(s, 3H), 3.86(s, 3H), 4.38(q, J=6.9Hz, 2H), 5.70(d, J=1.2Hz , 1H), 6.00(d, J=1.2Hz, 1H), 6.38(d, J=8.1Hz, 1H), 7.1 5(dd, J=7.5, 7.5Hz, 1H), 7.37(dd, J=8.4 , 1.5Hz, 1H), 7.41(dd, J=7.8, 7.2Hz, 1H), 7.48(d, J=8.4Hz, 1H), 7.55(d, J=8.4Hz, 1H), 7.78(d, J =8.1Hz, 1H), 8.08(d, J=1.5Hz, 1H), 8.11(d, J=7.8Hz, 1H).

[0106] 13 C NMR (DMSO-d 6 );

[0107] Elemental Analysis: C 22 h 22 N 2 o 3 S 0.25H 2 O. Calculated: C, 72.01; H, 6.19; N, 7.64. Found: C, 71.96; H, 6.20; N, 7.47.

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Abstract

The present invention provides one kind of new antitumor compound and its preparation process. The compound is heteroaromatic ring ketone (alcohol) or its derivative in the structure as shown. The compound of the present invention may be used in preparing tubulin inhibitor, and possesses antitumor effect. The present invention also provides antitumor medicine composition with the compound as the active component. The compound has the advantages of small molecular weight, simple synthesis process and less toxic side effect.

Description

technical field [0001] The invention relates to a new class of anti-tumor compounds (or called heteroaromatic ring ketones (alcohols) or derivatives thereof) and a preparation method thereof. The invention also provides an anti-tumor pharmaceutical composition containing the compounds as active ingredients. Background technique [0002] Tubulin inhibitors are a class of very effective antitumor drugs. With the widespread clinical application of paclitaxel (Paclitaxol and Docetaxol) and the in-depth understanding of the structure and function of microtubules, antitumor drugs targeting tubulin The research and development of tumor drugs has increasingly attracted the attention and interest of pharmaceutical companies and pharmacologists all over the world. [0003] Microtubules are the main components of the cytoskeleton, mainly assembled by α- and β-tubulin heterodimers. Microtubules are ubiquitous in eukaryotic cells and play an important role in maintaining cell shape, cel...

Claims

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Application Information

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IPC IPC(8): C07D209/86C07D401/12C07D209/12C07D307/80C07D333/56A61K31/4439A61K31/4433A61K31/403A61P35/00
CPCC07D209/86C07D209/12C07D401/06A61P35/00
Inventor 胡来兴大卫·W·博伊金李卓荣蒋建东
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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