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Multiple-target-point tamibarotene derivatives, preparation method and purposes thereof

A tamibarotene, multi-target technology, applied in the multi-target tamibarotene derivatives and their preparation, in the field of anti-malignant tumor (especially leukemia) drugs, can solve the problem of skin irritation and labor Protection conditions require high, low drug resistance and other issues

Inactive Publication Date: 2012-01-25
济南铂卅医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Tamibarotene (AM80) is the first marketed retinoic acid receptor α (RARα) subtype selective agonist, mainly used in clinical treatment Various types of relapsed or refractory acute promyelocytic leukemia (APL) (Gan To Kagaku Ryoho 33:397-401, 2006), which has a higher efficacy compared with all-trans retinoic acid (ATRA) However, its toxic and side effects including hypertriglyceridemia, hypercholesterolemia, rash, bone pain, retinoic acid syndrome and teratogenic effects limit its clinical use ( Drugs Today 43: 563-568, 2007)
In addition, the raw material of tamibarotene is more irritating to the skin, and the requirements for labor protection during the production of large quantities of preparations are high, resulting in increased production costs

Method used

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  • Multiple-target-point tamibarotene derivatives, preparation method and purposes thereof
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  • Multiple-target-point tamibarotene derivatives, preparation method and purposes thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Butyryl chloride ( 1a ) and 2-propylpentanoyl chloride ( 1b ) preparation

[0064] Add n-butyric acid (88.1g, 1.0mol) or valproic acid (144.2g, 1.0mol) to thionyl chloride (119.0g, 1.0mol), then add 0.1mL DMF as a catalyst, and stir the reaction at 60°C for 1 Hours, distill and collect n-butyryl chloride (collect 95~105°C fraction by atmospheric distillation) or 2-propylpentanoyl chloride (collect 75~85°C / 2.6kPa fraction by vacuum distillation) to obtain a colorless transparent liquid ( 1a ) (n-butyryl chloride, 99.7g, yield 93.6%) and ( 1b ) (2-propylpentanoyl chloride, 147.8g, yield 90.9%), which was directly used in the next reaction.

[0065]

Embodiment 2

[0066] Example 2: 2-Hydroxyethylbutyrate ( 2a ) and 2-hydroxyethyl-2-propylvalerate ( 2d ) preparation

[0067] Butyryl chloride ( 1a ) (10.7g, 0.1mol) or 2-propylpentanoyl chloride ( 1b ) (16.3g, 0.1mol) was dissolved in 50 mL of dichloromethane to obtain solution 1, and ethylene glycol (0.1mol) and triethylamine (15.2g, 0.15mol) were added to 100mL of dichloromethane to obtain solution 2. Slowly add solution 1 to solution 2 with stirring at room temperature, and the dropwise addition is completed within 2 hours, then stir at room temperature for 5 hours, concentrate under reduced pressure and distill off the solvent and excess triethylamine, the residue is separated by column chromatography, and the eluent is reduced to Concentrate under pressure to dryness to obtain pure product 2-hydroxyethyl butyrate ( 2a ) (yield 48.1%) and 2-hydroxyethyl-2-propylvalerate ( 2d ) (yield 54.8%), directly used in the next reaction.

[0068]

Embodiment 3

[0069] Example 3: N-(2-aminoethyl)butyramide ( 2g ) and N-(2-aminoethyl)-2-propylpentanamide ( 2h ) preparation

[0070] Ethylenediamine (0.1mol) and triethylamine (15.2g, 0.15mol) were added to 100mL of dichloromethane to obtain solution 1, n-butyryl chloride ( 1a ) (10.7g, 0.1mol) or 2-propylpentanoyl chloride ( 1b ) (16.3g, 0.1mol) was dissolved in 50 mL of dichloromethane to obtain solution 2. Slowly add solution 2 to solution 1 under stirring at room temperature, the dropwise addition is completed within 2 hours, then stir at room temperature for 3 hours, concentrate under reduced pressure to remove the solvent and excess triethylamine, the residue is separated by column chromatography, and the eluent is reduced to Concentrate under reduced pressure to dryness to obtain pure product N-(2-aminoethyl) butyramide ( 2g ) (yield 56.7%) and N-(2-aminoethyl)-2-propylpentanamide ( 2h ) (yield 63.5%), directly used in the next reaction.

[0071]

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PUM

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Abstract

The invention discloses multiple-target-point tamibarotene derivatives, a preparation method and purposes thereof. More specifically speaking, the invention provides a compound represented by a structural general formula (I), wherein the definition of R is referred to an instruction book; the derivatives are multiple-target-point compounds which are obtained by connecting tamibarotene as an RAR (retinoic acid receptors) excitant with various histone deacetylase inhibitors, various RXR (retinoid X receptors) excitants or other pharmacophoric groups directly through ester bonds or amido bonds or indirectly through connecting groups; and the derivatives are suitable to be used as antitumor drugs to be used for treating various malignant tumors, and are particularly suitable for treating various leukemia.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to multi-target tamibarotene derivatives and preparation methods thereof, as well as the medical application of these compounds, especially the application as anti-malignant tumor (especially leukemia) drugs. Background technique [0002] Histone deacetylases (HDAC) are a family of proteases that widely exist in various eukaryotic cells. Currently, there are 18 different subtypes, which can be divided into 4 major groups according to their structure and function. Class (I~IV). HDAC is one of the key factors involved in the regulation of gene transcription. It participates in the composition of the transcriptional co-repression complex and indirectly binds to the DNA of the target gene, catalyzing the deacetylation of the corresponding nucleosome histones, making the nucleosome structure compact. , which inhibits transcriptional co-repression complexes from binding DNA, th...

Claims

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Application Information

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IPC IPC(8): C07C233/80C07C259/06C07C259/10C07C233/65C07C231/12C07C231/02C07K5/093A61K31/167A61K31/245A61K38/06A61P35/00A61P35/02
Inventor 徐文方边海勇吴敬德王学健冯金红
Owner 济南铂卅医药科技有限公司
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