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Derivatives of naftifine hydrochloride as well as preparation method and application thereof

A technology of drugs and compounds, applied in the field of preparation of naftifine hydrochloride and its derivatives, can solve the problems of increasing bacterial resistance, increasing bacterial virulence, etc.

Active Publication Date: 2014-09-24
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are also some research reports that the golden yellow pigment can increase the resistance of bacteria to oleic acid. In the mouse subcutaneous infection model experiment, the abscess area caused by the mutant strain that cannot produce pigment is significantly smaller than that of the wild-type strain, suggesting that the pigment can increase the resistance of bacteria to oleic acid. Antioxidant ability to increase bacterial virulence

Method used

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  • Derivatives of naftifine hydrochloride as well as preparation method and application thereof
  • Derivatives of naftifine hydrochloride as well as preparation method and application thereof
  • Derivatives of naftifine hydrochloride as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0121] The preparation method of the compound of formula I of the present invention or its pharmaceutically acceptable salt, comprises the following steps:

[0122]

[0123] (a) compound of formula II reacts with compound of formula III to generate compound of formula I; and optionally

[0124]

[0125] (b) the step of generating the hydrochloride salt of the compound of formula I from the compound of formula I,

[0126] In each formula, Ar is a C6-C10 aryl group, a C6-C10 aryl group substituted by a C1-C6 alkyl group.

[0127] In another preferred example, Ar is phenyl, naphthyl, or phenyl substituted by C1-C6 alkyl.

[0128] In another preferred embodiment, Ar is Among them, R 1 , R 2 independently C1-C6 alkyl or hydrogen; or R 1 , R 2 Together with adjacent carbon atoms, they form a C6-C10 aryl group.

[0129] In another preferred example, R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, R 2 for hydrogen.

[0...

Embodiment 1

[0173] Embodiment 1N-methyl-naphthalene-1-methylamine (intermediate II)

[0174]

[0175] 10 ml of 20% methylamine aqueous solution was dissolved in 20 ml of tetrahydrofuran, and then a solution of 3 g of 1-(chloromethyl)naphthalene in 10 ml of tetrahydrofuran was slowly added dropwise to the reaction system, and reacted overnight at room temperature. After the reaction was completed, it was concentrated, and column chromatography gave the title compound (Intermediate II), 2.2 g of a yellow oil, with a yield of 75%.

[0176] 1 H-NMR (400MHz, acetone) δ8.23 (d, J = 7.9Hz, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 7.48 (ddd, J=22.4,14.0,7.1Hz,4H),4.17(s,2H),2.46(s,3H).

Embodiment 2

[0177] Example 2 Preparation of (E)-3-(4-methylphenyl)-prop-2-en-1-ol (intermediate IV-1).

[0178]

[0179] 100 mg of (E)-3-(4-methylphenyl)-acrolein was dissolved in 10 ml of methanol, and 26 mg of sodium borohydride was added in batches under ice cooling, and reacted at room temperature for 15 minutes. After concentration, water was added to the residue, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 99 mg of the title compound as an oil, with a yield of 98%. Directly cast the next reaction.

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Abstract

The invention discloses derivatives of naftifine hydrochloride as well as a preparation method and application thereof. The derivatives of naftifine hydrochloride are as shown in the formula I. By inhibiting expression and / or function of key catalyzing enzyme CrtN in a golden yellow pigment synthesis pathway and powerfully inhibiting synthesis of golden yellow pigment, virulence of bacteria can be lowered. The key catalyzing enzyme CrtN in the golden yellow pigment synthesis pathway can be taken as a drug acting target; and compounds capable of inhibiting expression and / or function of key catalyzing enzyme CrtN can be used for preparing anti-bacterial drug. The naftifine hydrochloride and the derivatives thereof can be used as inhibitors for catalyzing enzyme CrtN to powerfully inhibit synthesis of the golden yellow pigment, so that the virulence of staphylococcus aureus can be lowered, and therefore, the derivatives can be used for preparing the anti-bacterial drug, especially drug for resisting staphylococcus aureus infection.

Description

technical field [0001] The invention relates to the fields of pharmacology, medicinal chemistry and drug therapeutics, and more specifically relates to naftifine hydrochloride and its derivatives, a preparation method, a new antibacterial application, and a target CrtN for exerting an antibacterial effect. Background technique [0002] Staphylococcus aureus is an important pathogen that seriously endangers human life and health. As a representative of Gram-positive bacteria, it is the most common pathogen causing suppurative infection in humans, which can directly lead to local suppurative infection, pneumonia, pseudomembranous enteritis, pericarditis, etc., and even systemic infection such as sepsis and sepsis. [0003] With the development of life science and medicine, it has been found that pathogenic bacteria, including Staphylococcus aureus, are pathogenic because they produce various virulence factors (Virulence factors) to help bacteria colonize, adhere, cytotoxicity,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/137A61P31/04C07C211/30C07C209/08C07C209/00C12N1/20C12Q1/14C12R1/445
CPCA61K31/137C07C209/00C07C209/08C07C211/30C12N1/20C12Q1/14C12N1/205C12R2001/445
Inventor 蓝乐夫李剑陈菲菲王友鑫蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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