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C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof

A technology of quinolone dimer and oxadiazole, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems that have not been reported, and achieve the effects of strong anti-tumor activity, strong growth inhibitory activity, and strong cytotoxicity

Inactive Publication Date: 2010-02-10
河南省健康伟业生物医药研究股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing FQ anti-tumor compounds all contain one FQ unit, and compounds containing two FQ structural units in one molecule have not been reported yet. In addition, although 1,3,4-oxadiazoles have a large number of synthetic reports, but The research using FQ skeleton as substituent has not been reported yet

Method used

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  • C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof
  • C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof
  • C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Preparation of 1-ethyl-6-fluoro-7-piperazin-1-yl-4(1H)-quinolinone-3-carboxhydrazide (norfloxacin hydrazide 1)

[0039] Norfloxacin (50 g, 157 mmol) was dissolved in 100 mL of 80% hydrazine hydrate, refluxed for 18 hours, cooled to room temperature, distilled under reduced pressure until evaporated to dryness, and the residue was recrystallized with 300 mL of absolute ethanol to obtain a yellow solid 1, Yield 74%. mp 186~187℃; IR(KBr)v: 3456, 2897, 1648, 1567, 1527, 1473, 1255, 869cm -1 ; 1 H NMR (DMSO-d 6 )δ: 10.56 (brs, 1H, CONH), 8.86 (s, 1H, 2-H), 7.86 (d, 1H, 5-H), 7.24 (d, 1H, 8-H), 4.53 (brs, 2H , NH 2 ), 4.62 (q, 2H, NCH 2 ), 3.32(t, 4H, piperazine-H), 2.67(t, 4H, piperazine-H), 1.36(t, 3H, CH 3 ); MS m / z: 356 (M+Na), 334 (M+H); Anal.calcd for C 16 h 20 FN5 o 2 : C 57.65, H 6.05, N 21.01; found C 57.84, H 6.15, N 21.24.

Embodiment 2

[0041] Preparation of 1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4(1H)-quinolinone-3-carboxhydrazide (pefloxacin hydrazide 2)

[0042] Using pefloxacin as raw material, compound 2 was obtained by the same preparation method as in Example 1, with a yield of 68%. mp192~194℃; IR(KBr)v: 3387, 3025, 1638, 1557, 1525, 1456, 1255, 886cm -1 ; 1 H NMR (DMSO-d 6 )δ: 10.46 (brs, 1H, CONH), 8.87 (s, 1H, 2-H), 7.82 (d, 1H, 5-H), 7.32 (d, 1H, 8-H), 4.56 (brs, 2H , NH 2 ), 4.42 (q, 2H, NCH 2 ), 3.35(t, 4H, piperazine-H), 2.66(t, 4H, piperazine-H), 2.37(s, 3H, N-CH 3 ), 1.34(t, 3H, CH 3 ); MS m / z: 348 (M+H); Anal.calcd for C 17 h 22 FN 5 o 2 : C58.78, H 6.38, N 20.16; found C 58.94, H 6.20, N 20.40.

Embodiment 3

[0044] Preparation of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-4-(1H)-quinolinone-3-carboxhydrazide (ciprofloxacin hydrazide 3)

[0045] Using ciprofloxacin as raw material, compound 3 can be obtained according to the same preparation method as in Example 1, with a yield of 70%. mp226~227℃; IR(KBr)v: 3428, 3309, 2940, 2834, 1661, 1626, 1471cm -1 ; 1 H NMR (DMSO-d 6 )δ: 1.20~1.35(m, 4H, cyclopropane-H), 3.09~3.12(m, 4H, piperazine-H), 3.25~3.27(m, 4H, piperazine-H), 3.45~3.51(m, 1H , cyclopropane-H), 4.45 (brs, 2H, NH 2 ), 7.32(d, 1H, 8-H), 8.01(d, 1H, 5-H), 8.77(s, 1H, 2-H), 10.83(s, 1H, CONH); MS m / z: 346 (M+H); Anal.calcd for C 17 h 20 FN 5 o 2 : C 59.12, H 5.84, N 20.28; found C 59.36, H 5.67, N 20.46.

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Abstract

The invention discloses a C3 / C3 fluoroquinolone dimmer derivative using oxadiazole as a connection chain as well as a preparation method and an application thereof. The C3 / C3 fluoroquinolone dimmer derivative using oxadiazole as a connection chain is a compound which has the following structural general formula (I), wherein R1 and R1' are independently selected from H, (C1-C10) alkyl, (C3)-(C10) cycloalkyl, (C1)-(C10) haloalkyl and substituted aryl group or substituted heterocyclic aryl group; R2 and R2' are independently selected from H, (C1-C7)alkyl, (C3)-(C7) cycloalkyl, substituted aryl group, substituted heterocyclic aryl group and hydrocarbon acyl or sulfonyl; R3 and R3' are independently selected from H, (C1-C5) alkyl, (C3)-(C5) cycloalkyl, substituted aryl radical or substitutionalheterocyclic aryl radical; and X and Y are independently selected from CH, N or carbon atoms connected with halogen, alkyl, oxyl, sulfenyl, amino, substituted amino, substituted aryl radical or substituted heterocyclic aryl radical. The C3 / C3 fluoroquinolone dimmer derivative using oxadiazole as a connection chain can be used for preparing medicaments for treating tumors and preventing microbialinfection diseases.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a C3 / C3 fluoroquinolone dimer derivative with oxadiazole as a linking chain, a preparation method thereof, and an application as a medicine for preparing tumors and antimicrobial infection diseases. Background technique [0002] Fluoroquinolones (FQ) are clinical antimicrobials developed in the 1980s, represented by norfloxacin, and nearly 30 varieties have been widely used clinically. The action target of fluoroquinolones topoisomerase (TOPO) has homologous sequence similarity with TOPO of mammals, and TOPO is also a new target of antitumor drug action. Accordingly, it is important to convert antibacterial drug FQ into antitumor drug FQ A new direction of current research. At present, anti-tumor FQ compounds including bicyclic quinolones, tricyclic quinolones, tetracyclic quinolones, chiral quinolones, flavonoids and other anti-tumor FQ compounds have ...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D498/06C07D513/06C07D519/00A61K31/496A61K31/5383A61K31/542A61P35/00A61P31/00
Inventor 胡国强谢松强侯莉莉孙茂峰张俊珂杨勇伊磊
Owner 河南省健康伟业生物医药研究股份有限公司
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