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Pyronaridine compounds and applications thereof

A kind of pyronaridine and compound technology, applied in the field of antimalarial pyronaridine compounds

Inactive Publication Date: 2014-02-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, unlike chloroquine, under the same conditions, the required drug concentration of pyronaridine is only 1 / 100 of that of chloroquine, and it has no obvious cross-resistance with piperaquine, hydroxypiperaquine and chloroquine. These facts suggest that There may be other sites or pathways of action of pyronaridine, so this issue deserves further research to prove

Method used

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  • Pyronaridine compounds and applications thereof
  • Pyronaridine compounds and applications thereof
  • Pyronaridine compounds and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0059] Example 12-methoxy-7-chloro-10-(3',5'-bis 3"-methyltetrahydropyrromethene-4'-hydroxyphenyl)aminobenzo[b]-1 , Preparation of 5-naphthyridine (compound PYR_90)

[0060] Mix 0.003 mole of 2-methoxy-7-chloro-10-(4'-hydroxyphenyl)aminobenzo[b]-1,5-naphthyridine with 5 ml of formaldehyde solution and 0.008 mole of 3-formaldehyde Dipyrrole was heated under reflux in 10 ml of 95% ethanol for 6 hours, filtered while it was hot, the filtrate was left to cool, and crystals were precipitated, collected crystals, recrystallized with acetone, weighing 0.99 g, yield 60.4%, melting point 168-170 ° C, 1 H-NMR ((CD 3 ) 2 SO)δ:9.05(s,1H,Ar-NH),8.21-6.71(m,7H,Ar-H),4.04(s,3H,OCH 3 ), 3.36 (s, 4H, Ar- CH 2 N),2.86(m,2H,N( CH 2 CH 2 CHCH 2 )CH 3 ),2.50(m,2H,N(CH 2 CH 2 CH CH 2 ) CH 3 ),2.16(m,2H,N( CH 2 CH 2 CHCH 2 )CH 3 ),1.94(m,2H,N(CH 2 CH 2 CH CH 2 )CH 3 ),1.67(m,4H,N(CH 2 CH 2 CHCH 2 ) CH 3 ),1.60(m,2H,N(CH 2 CH 2 CH CH 2 )CH 3 ),1.05(d,6H,N...

Embodiment 22

[0061] Example 22-Methoxy-7-chloro-10-(3',5'-bis-hexahydropiperidinium-4'-hydroxyphenyl)aminobenzo[b]-1,5-naphthalene Preparation of pyridine (compound PYR_98)

[0062] In addition to using piperidine instead of 3-methylpyrrole, the compound 2-methoxy-7-chloro-10-(3',5'-bis-hexahydropiperidinylmethine was synthesized according to the similar synthetic route in Example 1 -4'-Hydroxyphenyl)aminobenzo[b]-1,5-naphthyridine (compound PYR98), yield 53.4%, melting point 165-166℃ 1H-NMR ((CD 3 ) 2 SO)δ:9.02(s,1H,Ar-NH),8.20-6.81(m,7H,Ar-H),4.04(s,3H,OCH 3 ), 3.38 (s, 4H, Ar- CH 2 N),2.86(m,8H,N( CH 2 CH 2 CH 2 CH 2 CH 2 )),1.92(m,8H,N(CH 2 CH 2 CH 2 CH 2 CH 2 )),1.57(m,4H,N( CH 2 CH 2 CH 2 CH 2 CH 2 ));LC-MS:C 31 h 36 ClN 5 o 2 [M+1] + 546.20

Embodiment 32

[0063] Example 32-Methoxy-7-chloro-10-(3',5'-bis 4''-methylhexahydropiperidinium-4'-hydroxyphenyl)aminobenzo[b] Preparation of -1,5-naphthyridine (compound PYR_99)

[0064] Except that 4-methylpiperidine was used instead of 3-methylpyrrole, the compound 2-methoxy-7-chloro-10-(3',5'-bis4"- Preparation of methylhexahydropiperidinium-4'-hydroxyphenyl)aminobenzo[b]-1,5-naphthyridine (compound PYR99), yield 60.4%, melting point 172-174°C 1 H-NMR ((CD 3 ) 2 SO)δ:9.05(s,1H,Ar-NH),8.21-6.71(m,7H,Ar-H),4.04(s,3H,OCH 3 ), 3.36 (s, 4H, Ar- CH 2 N),2.86(m,8H,N( CH 2 CH 2 CHCH 2 CH 2 )CH 3 ),1.94(m,8H,N(CH 2 CH 2 CH CH 2 CH 2 )CH 3 ),1.60(m,2H,N ( CH 2 CH 2 CH CH 2 CH 2 )CH 3 ),1.00(d,6H,N(CH 2 CH 2 CHCH 2 CH 2 )CH 3 );LC-MS:C 33 h 40 ClN 5 o 2 [M+1] + 574.15

[0065] Examples of biological activity testing experiments:

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Abstract

The invention provides pyronaridine compounds and applications thereof. The general formula of the pyronaridine compounds is shown as the formula I, wherein R1, R2, R3, and R4 are acting sites, and therefore the compounds have activity of inhibiting plasmodium in-vivo PDE. The pyronaridine compounds have a binding free energy lower than pyronaridine, and therefore the pyronaridine compounds have higher activity of inhibiting the plasmodium in-vivo PDE than the pyronaridine, and therefore the pyronaridine compounds have stronger anti-malarial activity.

Description

technical field [0001] The present invention relates to a pyronaridine compound and its use, in particular to a pyronaridine structure optimization to make it have lower binding free energy and higher inhibition of PDE (phosphodiesterase) in Plasmodium. ) active antimalarial pyronaridines. Background technique [0002] Pyronaridine (PYR) is a Plasmodium erythrocytic anamorphic agent created in my country in 1970, code-named 7351. The chemical name of the corresponding drug is 2-methoxy-7-chloro-10-[3′,5′-bis(pyrrolidinyl-1-methyl)-4′-hydroxy-phenyl]aminobenzo[ b] 1,5-naphthyridine tetraphosphate, the trade name is malaridine, and the molecular formula is: [0003] [0004] PYR can effectively act on Plasmodium falciparum. The order of sensitivity to pyronaridine at different developmental stages of the red inner stage protozoa is ring body > trophozoite > schizont, and the effect on pyronaridine is greater than that of chloroquine on all stages of protozoa. [00...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4745A61P33/06
CPCC07D471/04Y02A50/30
Inventor 朱维良张皓冰王贺瑶胡薇蔡海燕段李平姚俊敏陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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