Novel ethylene diamine derivative

A crystal form, ethyl technology, applied in the preparation of carbamate derivatives, the preparation of amino compounds from amines, the preparation of organic compounds, etc., can solve the problems of serious adverse reactions, optic nerve damage, low oral bioavailability, etc. Effects of improved bioavailability, overcoming severe obstacles, good pharmacokinetic properties

Inactive Publication Date: 2009-07-01
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This treatment method has the following disadvantages: the treatment cycle is long, usually more than 1 year, which is caused by the insensitivity of latent Mycobacterium tuberculosis to drugs; the adverse reactions are relatively serious, such as the combination of rifampicin and isoniazid may cause severe In liver disease, ethambutol can cause optic nerve damage; in particular, existing drugs are poorly or ineffectively treating rapidly spreading multidrug-resistant tuberculosis (MDR-TB)
However, due to the serious first-pass effect of SQ109, its oral bioavailability is very low [British Journal of Pharmacology, 2006, 1-10; Current Medicinal Chemistry, 2008, 15, 809-825], which seriously limits its clinical application. prospect

Method used

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  • Novel ethylene diamine derivative
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: (E)-N-(3,7-Dimethyl-octa-2,6-dienyl)-N-(2-(adamantan-2-ylamino)ethyl)-carbamic acid (pivaloyloxy)methyl ester (Compound I-a)

[0122] method one

[0123] (E)-N-(3,7-Dimethyl-octa-2,6-dienyl)-N'-(adamantan-2-yl)-ethane-1,2-diamine (700mg, 2.12mmol) was dissolved in 20mL THF, added triethylamine (642mg, 6.36mmol) and cooled to 0°C in an ice bath, then added dropwise (pivaloyloxy)methyl chloroformate (413mg, 2.12mmol), and recovered after dropping Stir at room temperature for 2h. Add 75 mL of water, extract with ethyl acetate (50 mL×2), wash with saturated brine, and dry over sodium sulfate. The desiccant was filtered off, concentrated, and column chromatography (petroleum ether: ethyl acetate = 3:1) gave a light yellow liquid (543 mg, yield 52.5%).

[0124] 1 H NMR (400MHz CDCl 3 )δ: 1.18(s, 9H), 1.42-1.47(m, 3H), 1.58(s, 3H), 1.62-1.70(m, 9H), 1.72-1.84(m, 6H), 1.85-2.08(m, 6H), 2.60-2.75(m, 3H), 3.28(t, J=6.59Hz, 1H), 3.36(t, J=6.59Hz, 1H), 3.88(d, J=6...

Embodiment 2

[0138] Example 2: (E)-N-(3,7-Dimethyl-oct-2,6-dienyl)-N-(2-(adamantan-2-ylamino)ethyl)-carbamic acid (pivaloyloxy)methyl ester maleate (compound I-b)

[0139] Compound I-a (250 mg) was dissolved in 5 mL of isopropanol, and maleic acid (59 mg) was added. Stir at room temperature for 0.5 h, and concentrate to give a white solid (310 mg, yield 100%).

[0140] Mp: 164-166°C; 1 H NMR (400MHz DMSO) δ: 1.44(s, 9H), 1.56-1.74(m, 15H), 1.84-2.09(m, 12H), 3.01-3.09(m, 2H), 3.45-3.51(m, 3H) , 3.83-3.90(m, 2H), 5.06-5.11(m, 2H), 5.71(s, 2H), 6.03(s, 2H), 8.31(brs, 2H); MS(ESI): 489

Embodiment 3

[0141] Example 3: (E)-N-(3,7-Dimethyl-oct-2,6-dienyl)-N-(2-(adamantan-2-ylamino)ethyl)-carbamic acid (pivaloyloxy)methyl ester mesylate (compound I-c)

[0142] Compound I-a (250 mg) was dissolved in 5 mL of isopropanol, and methanesulfonic acid (49 mg) was added. Stir at room temperature for 0.5 h, and concentrate to obtain a white solid (293 mg, yield 98%).

[0143] Mp: 173-175°C; MS (ESI): 489

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Abstract

The invention relates to ethylenediamine compounds of which the structural formula is as shown in a formula (I), pharmaceutically acceptable salts, a preparation method thereof and application of the ethylenediamine compounds in preparing medicines for treating infectious diseases caused by tubercle bacillus and particularly infectious diseases caused by multidrug resistant tubercle bacillus. The compounds of which the structural formula is shown in the (I) have good in vitro tubercle bacillus resistant activity and good in vivo pharmacokinetics property.

Description

technical field [0001] The invention belongs to the field of pharmacy, relates to the fields of medicinal chemistry, pharmacology and pharmacokinetics, more specifically, relates to an anti-tuberculosis drug and a preparation method thereof and in the preparation and treatment of infectious diseases, especially the infectivity caused by Mycobacterium tuberculosis. Use in disease medicine. Background technique [0002] Tuberculosis is caused by Mycobacterium tuberculosis infection and is one of the oldest human diseases. Among human tuberculosis, the most common is pulmonary tuberculosis. Today, tuberculosis is still seriously endangering human health, and it is one of the infectious diseases that cause the largest number of deaths. According to WHO statistics, about 1 / 3 of the world's people have been infected with Mycobacterium tuberculosis. In 2005 alone, 1.6 million people died of tuberculosis worldwide. Tuberculosis is also one of the leading causes of death among AID...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/20C07C269/04C07D317/40A61K31/27A61K31/357A61P31/06
CPCC07C209/68A61K31/27C07D317/40C07C211/38A61K31/357A61P31/06
Inventor 孟庆义陈义朗刘亦斌罗会兵
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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