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Preparation method of ramosetron derivatives and applications thereof

A technology for drugs and compounds, applied in the field of medicine, can solve the problems of water solubility and unsatisfactory bioavailability of alkanoyl ramosetron compounds, and achieve the effects of good pharmacological activity, easy taking and fast drug absorption

Active Publication Date: 2011-06-22
天津康鸿医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in subsequent studies, we found that the water solubility and bioavailability of this kind of alkanoyl ramosetron compounds were not very ideal. In order to better solve these technical defects, we used the design technology of prodrugs in On the basis of the existing structure, the synthesis and screening research were carried out. The experimental results showed that the water solubility of the synthesized compounds was greatly improved, and some compounds showed better pharmacological activity in activity, which reached our Goals of prospective research

Method used

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  • Preparation method of ramosetron derivatives and applications thereof
  • Preparation method of ramosetron derivatives and applications thereof
  • Preparation method of ramosetron derivatives and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 5(R)-[(1-methylindol-3-yl)carbonyl]-1-(tert-butoxyformyl)glycyl-4,5,6,7-tetrahydrobenzimidazole (IV- 1) Preparation

[0051] Take 1g of 5(R)-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole (II) and 0.5g of Boc-glycine into 50ml In a round bottom flask, add 10ml tetrahydrofuran (THF), stir for 10 minutes, dissolve completely, add 1.4g of 1-hydroxy-benzo-triazole (HOBt), 1g of N,N'-dicyclohexylcarbonyl Amine (DCC), 1ml of triethylamine, dissolved. Under the condition of stirring at room temperature, a white solid gradually precipitated, reacted for 5 hours, the reaction was basically complete, filtered, and the filtrate was evaporated to dryness to obtain an oily substance, added 30ml of ethyl acetate, added 20ml of water, added a small amount of acid water dropwise, and adjusted the pH value to about 4 -5 or so, stirred at room temperature for 0.5 hours, and filtered. The extraction was repeated 3 times with 30 ml of ethyl acetate. The ethy...

Embodiment 2

[0052] Example 2 Preparation of 5(R)-[(1-methylindol-3-yl)carbonyl]-1-glycyl-4,5,6,7-tetrahydrobenzimidazole (I-1)

[0053] Put 1.2 g of the crude product (IV-1) of Example 1 into a 50 ml round-bottomed flask, add 25 ml of dichloromethane, stir for 5 minutes, after complete dissolution, add 1.09 g of trifluoroacetic acid dropwise, and stir at room temperature for 4 hours. Stop the reaction, add 30ml of water, adjust the pH value to greater than 9 with aqueous sodium hydroxide solution, then add 30ml of ethyl acetate, repeat the extraction 3 times, separate the ethyl acetate layer, and dry it with anhydrous magnesium sulfate overnight. The next day, suction filtration under reduced pressure, the filtrate was concentrated to dryness to obtain 0.62 g of a light yellow solid, which was separated by a column to obtain 0.3 g of a light yellow solid (I-1), detected by TCL, R f 0.3 (developing solvent: ethyl acetate / ethanol = 1:1), yield 32.4%. 1 HNMR (DMSO-d 6 ), δ(ppm): 1.5-2.0(...

Embodiment 3-7

[0055] According to the same method as in Example 1, the difference is that (III) compounds of different structures and 5(R)-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydro Benzimidazole (II) was reacted, and the reaction temperature and reaction time were prepared with reference to the following Table 1 to obtain the compound of the following formula (IV). The results are shown in Table 1.

[0056] Table 1

[0057] Example

(III)

(IV)

reaction

temperature

reaction

time

code name

3

Boc-preserved

amino acid

5(R)-[(1-methylindol-3-yl)carbonyl]-1-

(tert-butoxyformyl)prolyl-4,5,6,

7-tetrahydrobenzimidazole

50℃

8 hours

(IV-2)

4

Boc-filament

amino acid

5(R)-[(1-methylindol-3-yl)carbonyl]-1-

(tert-butoxyformyl)seryl-4,5,6,

7-Tetrahydrobenzimidazole

room temperature

5 hours

(IV-3)

5

Bo...

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PUM

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Abstract

The invention relates to a preparation method of ramosetron derivatives and applications thereof. The invention provides a compound as expressed in the formula (I), a pharmaceutically acceptable salt thereof, an enantiomer or racemic mixture thereof, wherein, R1 is H, C1-C6 alkyl, C1-4 alkyloxys, aryls or substituted C1-C4 alkyl. The invention also provides a preparation method of the compound or the pharmaceutically acceptable salt thereof, the pharmaceutical composition containing the compound and the salt, and applications of the compound. The compound in the invention possesses functions of preventing and treating the digestive tract symptoms of nausea, vomit, etc. caused by anti-malignant tumor treatment, and preventing and treating irritable bowel syndrome. The compound can be used in preparing medicine for preventing and treating the digestive tract symptoms of nausea, vomit, etc. caused by anti-malignant tumor treatment, and irritable bowel syndrome.

Description

technical field [0001] The invention belongs to the technical field of medicine, specifically, the invention relates to a novel ramosetron derivative or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, a preparation method and a pharmaceutical composition thereof, and Its use in the preparation of medicines for preventing and treating nausea, vomiting and other gastrointestinal symptoms and irritable bowel syndrome caused by anti-malignant tumor treatment. Background technique [0002] Ramosetron hydrochloride is a new generation of powerful and highly selective 5-HT3 receptor antagonist, mainly by blocking the 5-HT3 receptors transmitted to the vagus nerve endings in the digestive tract mucosa, and it can treat the nausea and vomiting caused by chemotherapy. And other gastrointestinal reactions play a significant role in control. Ramosetron was launched in 1996, and a large number of clinical trials have confirmed that it is mainly...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/4184A61P1/08A61P1/00
Inventor 李袆亮邹美香岳南李鹏旺石玉孙歆慧陈芙蓉吴疆只德广张彩霞赵益桂
Owner 天津康鸿医药科技发展有限公司
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