CN102391287B - Levo-fluoroquinolone C3 bisazole methyl sulfide, preparation method and application thereof - Google Patents
Levo-fluoroquinolone C3 bisazole methyl sulfide, preparation method and application thereof Download PDFInfo
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- CN102391287B CN102391287B CN 201110296594 CN201110296594A CN102391287B CN 102391287 B CN102391287 B CN 102391287B CN 201110296594 CN201110296594 CN 201110296594 CN 201110296594 A CN201110296594 A CN 201110296594A CN 102391287 B CN102391287 B CN 102391287B
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- YRLGBNYSGBAJRH-JTQLQIEISA-N C[C@@H](COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3c([o]4)nnc4S)c1c2C3=O Chemical compound C[C@@H](COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3c([o]4)nnc4S)c1c2C3=O YRLGBNYSGBAJRH-JTQLQIEISA-N 0.000 description 1
- FHMFBBPKXXZOOM-ZDUSSCGKSA-N C[C@@H]1N(C=C(C(OC(S)=C)=C)C(c2cc(F)c3N4CCN(C)CC4)=C)c2c3OC1 Chemical compound C[C@@H]1N(C=C(C(OC(S)=C)=C)C(c2cc(F)c3N4CCN(C)CC4)=C)c2c3OC1 FHMFBBPKXXZOOM-ZDUSSCGKSA-N 0.000 description 1
- 0 C[C@@](COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3C(N[*+])=O)c1c2C3=O Chemical compound C[C@@](COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3C(N[*+])=O)c1c2C3=O 0.000 description 1
Abstract
The invention belongs to the technical field of medicine, and in particular discloses a levo-fluoroquinolone C3 bisazole methyl sulfide, a preparation method and application thereof in the field of pharmacy. The chemical structural formula of the levo-fluoroquinolone C3 bisazole methyl sulfide is shown as a general formula I, wherein in the general formula I, X is selected from any one of O, S and -NH; and Ar is selected from any one of phenyl, substituent-containing phenyl and heterocyclic aromatic hydrocarbon. The levo-fluoroquinolone C3 bisazole methyl sulfide has strong in vitro cytotoxin effect on experimental leukemia cancer cell strains, has strong anti-tumor activity, and can be mixed with a human acceptable acid salt or a medicinal carrier to prepare an anti-tumor medicament.
Description
Technical field
The present invention relates to medical technical field, be specifically related to levo-fluoroquinolone C 3 bisazole methyl sulfide, also relate to the preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide and in the application of pharmacy field simultaneously.
Background technology
Fluoroquinolone (FQ) is for take the clinical antimicrobial drug that Norxin (norfloxicin) develops as representative the eighties in last century.Have similar function based on its action target spot topoisomerase (TOPO) to Mammals TOPO, accordingly antibiotic FQ being converted into to antitumor FQ is a new direction of studying at present.Although designed and synthesized structure and comprise the antitumor FQ compounds such as two ring quinolones, three ring quinolones, Fourth Ring quinolones, chirality quinolone, flavonoid class, but at present these compounds having in varying degrees toxicity and active parallel, in body poor solubility cause bioavailability low, in vivo easily by common problem (Wang Xiaotian etc. urgently to be resolved hurrily such as metabolism inactivations, Chinese Pharmaceutical Journal, 2004,39,890).Therefore, find new structural modification approach, find that new lead compound is current problem demanding prompt solution.Recent studies on is at present found, though fluoroquinolone C-3 carboxyl is necessary to anti-microbial activity, but not necessary to anti-tumor activity, existing research is found with benzo five-membered fused heterocycle (You Qidong etc., Chinese patent, publication number is CN1473827A) or some other fused heterocycle (patent No. is 200910065991.0 for Hu Guoqiang etc., Chinese patent) replace the compound that fluoroquinolone C-3 carboxyl obtains and there is strong anti-tumor activity.In addition, though azole compounds has a large amount of synthetic reports, as the research of the isostere of levofloxacin C-3 carboxyl, there is not yet report.
Summary of the invention
The object of the present invention is to provide a kind of levo-fluoroquinolone C 3 bisazole methyl sulfide.
The present invention also aims to provide a kind of preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide.
The present invention also aims to provide a kind of application of levo-fluoroquinolone C 3 bisazole methyl sulfide.
In order to realize above purpose, the technical solution adopted in the present invention is: a kind of levo-fluoroquinolone C 3 bisazole methyl sulfide, and chemical structural formula is as shown in general formula I:
General formula I,
Wherein, X be selected from O, S ,-any in NH;
Ar is selected from phenyl, containing any in substituent phenyl, heteroaromatic alkyl.
Preferably, Ar is selected from any in phenyl, alkoxyl phenyl, alkyl phenyl, halogenophenyl, nitrophenyl.
Further preferred, Ar is selected from any in phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, p-nitrophenyl.
The preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide comprises the following steps:
(1) levofloxacin is dissolved in the hydrazine hydrate that excessive mass percent concentration is 80%, then back flow reaction is 12～24 hours, makes the levofloxacin hydrazides, and the chemical structural formula of levofloxacin hydrazides is suc as formula shown in B;
(2) take the levofloxacin hydrazides makes compound shown in general formula I I as raw material;
(3) shown in general formula I I, compound shown in compound and general formula III carries out condensation under acidity or alkaline condition, make levo-fluoroquinolone C 3 bisazole methyl sulfide, the chemical structural formula of levo-fluoroquinolone C 3 bisazole methyl sulfide is as shown in general formula I, and wherein shown in general formula I I, the mol ratio of compound shown in compound and general formula III is: compound shown in general formula I I: compound shown in general formula III=1: (1.2～1.3);
Formula B
General formula I I general formula III
General formula I.
Further, in step (2), when the X in compound shown in general formula I I is O, shown in general formula I I, the structural formula of compound is formula C:
Formula C,
The preparation method of compound shown in formula C is: first the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, and then drip dithiocarbonic anhydride in the ethanolic soln of potassium hydroxide, normal-temperature reaction is 3 hours afterwards, then reflux is dissolved the solid in reaction system fully, decompression and solvent recovery is to dry afterwards, add water in residuum, use the gac reflux decolour, filter, filtrate is adjusted to neutrality with hydrochloric acid, there is solid to separate out, the solid of separating out washes with water, drying obtains compound shown in formula C again, levofloxacin hydrazides wherein, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1: 1.5: 1.5.
In step (2), the X in compound shown in general formula I I is-during NH, shown in general formula I I, the structural formula of compound is formula D:
Formula D,
The preparation method of compound shown in formula D is: the levofloxacin hydrazides is dissolved in the dilute hydrochloric acid that mass percent concentration is 6%, add potassium thiocyanate afterwards in described dilute hydrochloric acid, then back flow reaction is 12 hours, filter, the gained filter cake is dissolved in the aqueous sodium hydroxide solution that mass percent concentration is 8% again, then back flow reaction is 6 hours, use afterwards activated carbon decolorizing, filter, filtrate is adjusted to neutrality with hydrochloric acid, separate out solid, the solid of separating out washes with water, drying again, obtain compound shown in formula D, wherein the mol ratio of levofloxacin hydrazides and potassium thiocyanate is: the levofloxacin hydrazides: potassium thiocyanate=1: 1.5.
In step (2), when the X in compound shown in general formula I I is S, the structural formula of compound shown in general formula I I is formula E:
Formula E,
The preparation method of compound shown in formula E is: the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, be placed in afterwards ice bath, drip dithiocarbonic anhydride again in the ethanolic soln of potassium hydroxide, then normal-temperature reaction is 24 hours, filter, filter cake is through washing, dry, milled processed, join afterwards in the vitriol oil of 0～10 ℃, being stirred to solid materials in 0～10 ℃ dissolves fully, then rising to stirring at normal temperature spends the night, pour into afterwards in the ethanol of 0 ℃, fully stir, placement is spent the night, filter, the gained filter cake is soluble in water, activated carbon decolorizing, filter, filtrate is adjusted to neutrality, separate out solid, the solid of separating out washes with water, dry, obtain compound shown in formula E, levofloxacin hydrazides wherein, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1: 1.5: 1.5.
In step (3), the preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide is:
Compound shown in compound shown in general formula I I and general formula III is put into to the aqueous ethanolic solution that mass percent concentration is 85%～95%, stirring and dissolving, be adjusted to slightly acidic, and back flow reaction is 12～24 hours afterwards, then evaporated under reduced pressure solvent, the residuum water dissolution, activated carbon decolorizing, filter, the filtrate adjust pH is to alkalescence, then use chloroform extraction, extraction liquid, through washing, dry, concentrated, obtains levo-fluoroquinolone C 3 bisazole methyl sulfide;
Perhaps compound shown in general formula I I is put into to DMF, and then add sodium carbonate, stirring at normal temperature 1 hour, add afterwards compound shown in general formula III, be stirred to compound shown in general formula I I and dissolve fully, then be poured into water, use chloroform extraction, extraction liquid, through washing, dry, concentrated, obtains levo-fluoroquinolone C 3 bisazole methyl sulfide.
Levo-fluoroquinolone C 3 bisazole methyl sulfide provided by the invention has stronger Vitro Cytotoxicity to the experimental leukemia JEG-3, show to there is strong anti-tumor activity, can be by with the acceptable sour salify of human body or be mixed with antitumor drug with pharmaceutical carrier.
Embodiment
Below by specific embodiment, technical scheme of the present invention is elaborated.
Embodiment 1-15 is the specific embodiment of levo-fluoroquinolone C 3 bisazole methyl sulfide.
Embodiment 1
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 2
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 3
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 4
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 5
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 6
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 7
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 8
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 9
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 10
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 11
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 12
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 13
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 14
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones, structural formula is:
Embodiment 15
(S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones, structural formula is:
Be below levo-fluoroquinolone C 3 bisazole methyl sulfide preparation method's specific embodiment, at first prepare following compound.
(1) prepare the levofloxacin hydrazides
The structural formula of levofloxacin hydrazides is formula B, and its preparation method is:
Formula B
Take the 57g levofloxacin, afterwards the levofloxacin taken is put into to the hydrazine hydrate that the 100mL mass percent concentration is 80%, back flow reaction 18 hours, be cooled to room temperature, underpressure distillation is until evaporate to dryness, and 300mL dehydrated alcohol recrystallization for residuum, obtain the levofloxacin hydrazides.
(2) preparation (S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl)-4 (1H)-quinolinones
(S)-8,1-[1,2-(oxygen propyl group)]-structural formula of the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl)-4 (1H)-quinolinones is formula C, its preparation method is:
Formula C
2.8g potassium hydroxide is dissolved in 200mL ethanol, make the ethanolic soln of potassium hydroxide, afterwards 10g levofloxacin hydrazides (26.7mmol) is dissolved in the ethanolic soln of potassium hydroxide, and then dropping dithiocarbonic anhydride (3.0g, 40.0mmol), stirring at normal temperature 3 hours, then reflux to solid materials dissolves fully, then decompression and solvent recovery is to dry, add water 300mL in residuum, use afterwards appropriate gac reflux decolour 1 hour, filter, remove gac, filtrate is used hydrochloric acid adjust pH to 7, now there is solid to separate out, the solid of separating out washes with water, dry, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinone crude products, be directly used in the next step.
(3) preparation (S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones
(S)-8,1-[1,2-(oxygen propyl group)]-structural formula of the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones is formula D, its preparation method is:
Compound 1
Formula D
10g levofloxacin hydrazides (26.7mmol) is dissolved in the dilute hydrochloric acid that the 200mL mass percent concentration is 6%, and then add 4.0g potassium thiocyanate (40.0mmol), back flow reaction 12 hours, filter afterwards, the crude product that filter cake is compound 1, filter cake is dissolved in the aqueous sodium hydroxide solution that the 200mL mass percent concentration is 8%, reflux 6 hours, use afterwards appropriate gac reflux decolour 1 hour, filter, filtrate is used hydrochloric acid adjust pH to 7, separate out solid, the solid of separating out washes with water, dry, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl)-4 (1H)-quinolinone crude products, be directly used in the next step.
(4) preparation (S)-8,1-[1,2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones
(S)-8,1-[1,2-(oxygen propyl group)]-structural formula of the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones is formula E, its preparation method is:
Compound 2
Formula E
2.8g potassium hydroxide is dissolved in 200mL ethanol, make the ethanolic soln of potassium hydroxide, afterwards 10g levofloxacin hydrazides (26.7mmol) is dissolved in the ethanolic soln of potassium hydroxide, be placed in afterwards under ice bath and drip dithiocarbonic anhydride (3.0g, 40.0mmol), stirring at normal temperature 24 hours, filter, filter cake washs with anhydrous diethyl ether, dry compound 2 crude products that obtain, afterwards by compound 2 crude product grind into powders, slowly joining the 100mL temperature is in the cold vitriol oil of 5 ℃ of left and right, then at this temperature, insulated and stirred to solid materials dissolves fully, and then rise to stirring at normal temperature and spend the night, in the ethanol that slowly to pour afterwards the 500mL temperature into be 0 ℃, fully stir, placement is spent the night, filter, the gained filter cake is (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl) vitriol of-4 (1H)-quinolinones, the gained filter cake is dissolved in 50mL water, add appropriate gac reflux decolour 0.5 hour, filter, filtrate is adjusted to neutrality with ammoniacal liquor, separate out solid, the solid of separating out washes with water, dry, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone crude products, be directly used in the next step.
Embodiment 16-30 is levo-fluoroquinolone C 3 bisazole methyl sulfide preparation method's specific embodiment.
Embodiment 16
The present embodiment is the embodiment of the compound that provides of Preparation Example 1, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinones (1.2mmol) are suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 85%, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then add 2-chloromethyl-5-phenyl-1, 3, 4-oxadiazole (0.3g, 1.5mmol), then back flow reaction is 12 hours, the evaporated under reduced pressure solvent, residuum adds water 30mL and dissolves, with appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product is used the dehydrated alcohol recrystallization again, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-oxadiazole-2-yl]-4 (1H)-quinolinone products, yield 72%, m.p.171～172 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.25 (s, 1H, C
2-H), 8.01 (d, J=7.3Hz, 2H, Ph-H), 7.54～7.45 (m, 4H, C
5-H and Ph-H), 4.74 (s, 2H, SCH
2), 4.54～4.39 (m, 3H, OCH
2cHN), 3.38 (br s, 4H, 2 * piperizine-CH
2), 2.58 (br s, 4H, 2 * piperizine-CH
2), 2.39 (s, 3H, NCH
3), 1.56 (d, J=6.6Hz, 3H, CH
3).
Embodiment 17
The present embodiment is the embodiment of the compound that provides of Preparation Example 2, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinones (1.2mmol) are suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 85%, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then add 2-chloromethyl-5-p-methoxyphenyl-1, 3, 4-oxadiazole (1.5mmol), then back flow reaction is 12 hours, the evaporated under reduced pressure solvent, residuum adds water 30mL and dissolves, with appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product is used the dehydrated alcohol recrystallization again, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-oxadiazole-2-yl]-4 (1H)-quinolinone products, yield 74%, m.p.173～175 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.36 (s, 1H, C
2-H), 8.05 (d, J=7.2Hz, 2H, Ph-H), 7.57～7.46 (m, 3H, C
5-H and Ph-H), 4.76 (s, 2H, SCH
2), 4.57～4.42 (m, 3H, OCH
2cHN), 3.82 (s, 3H, OCH
3), 3.44 (br s, 4H, 2 * piperizine-CH
2), 2.62 (br s, 4H, 2 * piperizine-CH
2), 2.41 (s, 3H, NCH
3), 1.57 (d, J=6.6Hz, 3H, CH
3).
Embodiment 18
The present embodiment is the embodiment of the compound that provides of Preparation Example 3, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinones (1.2mmol) are suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 85%, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then add 2-chloromethyl-5-p-methylphenyl-1, 3, 4-oxadiazole (1.5mmol), then back flow reaction is 12 hours, the evaporated under reduced pressure solvent, residuum adds water 30mL and dissolves, with appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product is used the dehydrated alcohol recrystallization again, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-oxadiazole-2-yl]-4 (1H)-quinolinone products, yield 68%, m.p.168～170 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.32 (s, 1H, C
2-H), 8.03 (d, J=7.2Hz, 2H, Ph-H), 7.62～7.50 (m, 3H, C
5-H and Ph-H), 4.74 (s, 2H, SCH
2), 4.53～4.40 (m, 3H, OCH
2cHN), 3.35 (br s, 4H, 2 * piperizine-CH
2), 2.57 (br s, 4H, 2 * piperizine-CH
2), 2.43 (s, 3H, NCH
3), 2.27 (s, 3H, Ph-CH
3), 1.55 (d, J=6.4Hz, 3H, CH
3).
Embodiment 19
The present embodiment is the embodiment of the compound that provides of Preparation Example 4, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinones (1.2mmol) are suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 85%, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then add 2-chloromethyl-5-rubigan-1, 3, 4-oxadiazole (1.5mmol), then back flow reaction is 12 hours, the evaporated under reduced pressure solvent, residuum adds water 30mL and dissolves, with appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product is used the dehydrated alcohol recrystallization again, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-oxadiazole-2-yl]-4 (1H)-quinolinone products, yield 81%, m.p.161～162 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.48 (s, 1H, C
2-H), 8.12 (d, J=7.2Hz, 2H, Ph-H), 7.68 (d, J=7.2Hz, 2H, Ph-H), 7.52 (d, J=7.6,1H, C
5-H), 4.78 (s, 2H, SCH
2), 4.56～4.43 (m, 3H, OCH
2cHN), 3.37 (br s, 4H, 2 * piperizine-CH
2), 2.62 (br s, 4H, 2 * piperizine-CH
2), 2.45 (s, 3H, NCH
3), 1.57 (d, J=6.4Hz, 3H, CH
3).
Embodiment 20
The present embodiment is the embodiment of the compound that provides of Preparation Example 5, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-oxadiazole-2-yl)-4 (1H)-quinolinones (1.2mmol) are suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 85%, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then add 2-chloromethyl-5-p-nitrophenyl-1, 3, 4-oxadiazole (1.5mmol), then back flow reaction is 12 hours, the evaporated under reduced pressure solvent, residuum adds water 30mL and dissolves, with appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product is used the dehydrated alcohol recrystallization again, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-oxadiazole-2-yl]-4 (1H)-quinolinone products, yield 76%, m.p.212～214 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.52 (s, 1H, C
2-H), 8.15 (d, J=7.2Hz, 2H, Ph-H), 7.72 (d, J=7.2Hz, 2H, Ph-H), 7.64 (d, J=7.6,1H, C
5-H), 4.82 (s, 2H, SCH
2), 4.58～4.45 (m, 3H, OCH
2cHN), 3.42 (br s, 4H, 2 * piperizine-CH
2), 2.65 (br s, 4H, 2 * piperizine-CH
2), 2.47 (s, 3H, NCH
3), 1.62 (d, J=6.4Hz, 3H, CH
3).
Embodiment 21
The present embodiment is the embodiment of the compound that provides of Preparation Example 6, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl) the 2-chloromethyl of-4 (1H)-quinolinones (1.2mmol) and 0.3g-5-phenyl-1, 3, 4-oxadiazole (1.5mmol) is suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 95%, then drip the 1.0mL glacial acetic acid, make reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent, add water 30mL dissolving in residuum, then use appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product anhydrous propanone recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1, 3, 4-oxadiazole-2-methylthio group)-4H-1, 2, 4-triazole-3-yl]-4 (1H)-quinolinone products, yield 68%, m.p.192～194 ℃,
1h NMR (DMSO-d
6, 400MHz) δ: 13.2 (br s, 1H, NH), 8.37 (s, 1H, C
2-H), 8.06 (d, J=7.3Hz, 2H, Ph-H), 7.62～7.50 (m, 4H, C
5-Hand Ph-H), 4.78 (s, 2H, SCH
2), 4.56～4.44 (m, 3H, OCH
2cHN), 3.45 (br s, 4H, 2 * piperizine-CH
2), 2.68 (br s, 4H, 2 * piperizine-CH
2), 2.41 (s, 3H, NCH
3), 1.57 (d, J=6.6Hz, 3H, CH
3).
Embodiment 22
The present embodiment is the embodiment of the compound that provides of Preparation Example 7, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl) the 2-chloromethyl of-4 (1H)-quinolinones (1.2mmol) and 1.5mmol-5-p-methoxyphenyl-1, 3, the 4-oxadiazole is suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 95%, then drip the 1.0mL glacial acetic acid, make reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent, add water 30mL dissolving in residuum, then use appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product anhydrous propanone recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1, 3, 4-oxadiazole-2-methylthio group)-4H-1, 2, 4-triazole-3-yl]-4 (1H)-quinolinone products, yield 68%, m.p.196～198 ℃,
1h NMR (DMSO-d
6, 400MHz) δ: 13.5 (br s, 1H, NH), 8.44 (s, 1H, C
2-H), 8.07 (d, J=7.2Hz, 2H, Ph-H), 7.66～7.48 (m, 3H, C
5-H and Ph-H), 4.78 (s, 2H, SCH
2), 4.62～4.45 (m, 3H, OC
h2CHN), 3.86 (s, 3H, OCH
3), 3.46 (br s, 4H, 2 * piperizine-CH
2), 2.68 (br s, 4H, 2 * piperizine-CH
2), 2.43 (s, 3H, NCH
3), 1.62 (d, J=6.6Hz, 3H, CH
3).
Embodiment 23
The present embodiment is the embodiment of the compound that provides of Preparation Example 8, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl) the 2-chloromethyl of-4 (1H)-quinolinones (1.2mmol) and 1.5mmol-5-p-methylphenyl-1, 3, the 4-oxadiazole is suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 95%, then drip the 1.0mL glacial acetic acid, make reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent, add water 30mL dissolving in residuum, then use appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, obtain crude product, crude product anhydrous propanone recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1, 3, 4-oxadiazole-2-methylthio group)-4H-1, 2, 4-triazole-3-yl]-4 (1H)-quinolinone products, yield 62%, m.p.180～182 ℃,
1h NMR (DMSO-d
6, 400MHz) δ: 13.1 (br s, 1H, NH), 8.38 (s, 1H, C
2-H), 8.06 (d, J=7.2Hz, 2H, Ph-H), 7.66～7.52 (m, 3H, C
5-H and Ph-H), 4.76 (s, 2H, SCH
2), 4.55～4.42 (m, 3H, OCH
2cHN), 3.38 (brs, 4H, 2 * piperizine-CH
2), 2.64 (br s, 4H, 2 * piperizine-CH
2), 2.45 (s, 3H, NCH
3), 2.32 (s, 3H, Ph-CH
3), 1.57 (d, J=6.4Hz, 3H, CH
3).
Embodiment 24
The present embodiment is the embodiment of the compound that provides of Preparation Example 9, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl) the 2-chloromethyl of-4 (1H)-quinolinones (1.2mmol) and 1.5mmol-5-rubigan-1, 3, the 4-oxadiazole is suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 95%, then drip the 1.0mL glacial acetic acid, make reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent, add water 30mL dissolving in residuum, then use appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, obtain crude product, crude product anhydrous propanone recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1, 3, 4-oxadiazole-2-methylthio group)-4H-1, 2, 4-triazole-3-yl]-4 (1H)-quinolinone products, yield 64%, m.p.173～175 ℃,
1h NMR (DMSO-d
6, 400MHz) δ: 13.6 (br s, 1H, NH), 8.52 (s, 1H, C
2-H), 8.15 (d, J=7.2Hz, 2H, Ph-H), 7.72 (d, J=7.2Hz, 2H, Ph-H), 7.54 (d, J=7.6,1H, C
5-H), 4.81 (s, 2H, SCH
2), 4.58～4.45 (m, 3H, OCH
2cHN), 3.44 (br s, 4H, 2 * piperizine-CH
2), 2.66 (br s, 4H, 2 * piperizine-CH
2), 2.47 (s, 3H, NCH
3), 1.64 (d, J=6.4Hz, 3H, CH
3).
Embodiment 25
The present embodiment is the embodiment of the compound that provides of Preparation Example 10, and its preparation method is:
By 0.5g (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1, 2, 4-triazole-3-yl) the 2-chloromethyl of-4 (1H)-quinolinones (1.2mmol) and 1.5mmol-5-p-nitrophenyl-1, 3, the 4-oxadiazole is suspended in the aqueous ethanolic solution that the 20mL mass percent concentration is 95%, then drip the 1.0mL glacial acetic acid, make reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent, add water 30mL dissolving in residuum, then use appropriate gac reflux decolour 1 hour, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product anhydrous propanone recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1, 3, 4-oxadiazole-2-methylthio group)-4H-1, 2, 4-triazole-3-yl]-4 (1H)-quinolinone products, yield 76%, m.p.223～225 ℃,
1h NMR (DMSO-d
6, 400MHz) δ: 13.8 (br s, 1H, NH), 8.72 (s, 1H, C
2-H), 8.24 (d, J=7.2Hz, 2H, Ph-H), 7.76 (d, J=7.2Hz, 2H, Ph-H), 7.68 (d, J=7.6,1H, C
5-H), 4.84 (s, 2H, SCH
2), 4.63～4.47 (m, 3H, OCH
2cHN), 3.46 (br s, 4H, 2 * piperizine-CH
2), 2.68 (br s, 4H, 2 * piperizine-CH
2), 2.50 (s, 3H, NCH
3), 1.64 (d, J=6.4Hz, 3H, CH
3).
Embodiment 26
The present embodiment is the embodiment of the compound that provides of Preparation Example 11, and its preparation method is:
(S)-8 by 0.5g, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved in 10mL DMF (N, dinethylformamide) in, add again 1.0g sodium carbonate, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, then add the 2-chloromethyl of 0.3g-5-phenyl-1, 3, 4-oxadiazole (1.5mmol), be stirred to (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in 50mL water, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product dehydrated alcohol recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-thiadiazoles-2-yl]-4 (1H)-quinolinone products, yield 64%, m.p.182～184 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.32 (s, 1H, C
2-H), 8.04 (d, J=7.3Hz, 2H, Ph-H), 7.58～7.44 (m, 4H, C
5-H and Ph-H), 4.78 (s, 2H, SCH
2), 4.57～4.41 (m, 3H, OCH
2cHN), 3.42 (br s, 4H, 2 * piperizine-CH
2), 2.62 (br s, 4H, 2 * piperizine-CH
2), 2.40 (s, 3H, NCH
3), 1.57 (d, J=6.6Hz, 3H, CH
3).
Embodiment 27
The present embodiment is the embodiment of the compound that provides of Preparation Example 12, and its preparation method is:
(S)-8 by 0.5g, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved in 10mL DMF (N, dinethylformamide) in, add again 1.0g sodium carbonate, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, then add the 2-chloromethyl of 1.5mmol-5-p-methoxyphenyl-1, 3, the 4-oxadiazole, be stirred to (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in 50mL water, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product dehydrated alcohol recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methoxyphenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-thiadiazoles-2-yl]-4 (1H)-quinolinone products, yield 77%, m.p.188～189 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.46 (s, 1H, C
2-H), 8.12 (d, J=7.2Hz, 2H, Ph-H), 7.75～7.52 (m, 3H, C
5-H and Ph-H), 4.82 (s, 2H, SCH
2), 4.64～4.46 (m, 3H, OCH
2cHN), 3.88 (s, 3H, OCH
3), 3.53 (br s, 4H, 2 * piperizine-CH
2), 2.68 (br s, 4H, 2 * piperizine-CH
2), 2.43 (s, 3H, NCH
3), 1.61 (d, J=6.6Hz, 3H, CH
3).
Embodiment 28
The present embodiment is the embodiment of the compound that provides of Preparation Example 13, and its preparation method is:
(S)-8 by 0.5g, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved in 10mL DMF (N, dinethylformamide) in, add again 1.0g sodium carbonate, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, then add the 2-chloromethyl of 1.5mmol-5-p-methylphenyl-1, 3, the 4-oxadiazole, be stirred to (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in 50mL water, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product dehydrated alcohol recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-methylphenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-thiadiazoles-2-yl]-4 (1H)-quinolinone products, yield 62%, m.p.190～192 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.52 (s, 1H, C
2-H), 8.07 (d, J=7.2Hz, 2H, Ph-H), 7.65～7.53 (m, 3H, C
5-H and Ph-H), 4.83 (s, 2H, SCH
2), 4.57～4.46 (m, 3H, OCH
2cHN), 3.48 (br s, 4H, 2 * piperizine-CH
2), 2.66 (br s, 4H, 2 * piperizine-CH
2), 2.45 (s, 3H, NCH
3), 2.32 (s, 3H, Ph-CH
3), 1.57 (d, J=6.4Hz, 3H, CH
3).
Embodiment 29
The present embodiment is the embodiment of the compound that provides of Preparation Example 14, and its preparation method is:
(S)-8 by 0.5g, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved in 10mL DMF (N, dinethylformamide) in, add again 1.0g sodium carbonate, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, then add the 2-chloromethyl of 1.5mmol-5-rubigan-1, 3, the 4-oxadiazole, be stirred to (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in 50mL water, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product dehydrated alcohol recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-thiadiazoles-2-yl]-4 (1H)-quinolinone products, yield 73%, m.p.182～184 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.57 (s, 1H, C
2-H), 8.16 (d, J=7.2Hz, 2H, Ph-H), 7.72 (d, J=7.2Hz, 2H, Ph-H), 7.58 (d, J=7.6,1H, C
5-H), 4.83 (s, 2H, SCH
2), 4.64～4.53 (m, 3H, OCH
2cHN), 3.46 (br s, 4H, 2 * piperizine-CH
2), 2.67 (br s, 4H, 2 * piperizine-CH
2), 2.46 (s, 3H, NCH
3), 1.63 (d, J=6.4Hz, 3H, CH
3).
Embodiment 30
The present embodiment is the embodiment of the compound that provides of Preparation Example 15, and its preparation method is:
(S)-8 by 0.5g, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved in 10mL DMF (N, dinethylformamide) in, add again 1.0g sodium carbonate, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, then add the 2-chloromethyl of 1.5mmol-5-p-nitrophenyl-1, 3, the 4-oxadiazole, be stirred to (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1, 3, 4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in 50mL water, chloroform extraction, washing, anhydrous sodium sulfate drying, obtain crude product, crude product dehydrated alcohol recrystallization, obtain (S)-8, 1-[1, 2-(oxygen propyl group)]-the fluoro-7-of 6-(4-methylpiperazine-1-yl)-3-[5-(5-p-nitrophenyl-1, 3, 4-oxadiazole-2-methylthio group)-1, 3, 4-thiadiazoles-2-yl]-4 (1H)-quinolinone products, yield 64%, m.p.227～229 ℃,
1h NMR (CDCl
3, 400MHz) δ: 8.68 (s, 1H, C
2-H), 8.24 (d, J=7.2Hz, 2H, Ph-H), 7.76 (d, J=7.2Hz, 2H, Ph-H), 7.68 (d, J=7.6,1H, C
5-H), 4.85 (s, 2H, SCH
2), 4.63～4.48 (m, 3H, OCH
2cHN), 3.46 (br s, 4H, 2 * piperizine-CH
2), 2.70 (br s, 4H, 2 * piperizine-CH
2), 2.46 (s, 3H, NCH
3), 1.67 (d, J=6.4Hz, 3H, CH
3).
The determination of cytotoxic activity of the levo-fluoroquinolone C 3 bisazole methyl sulfide compound that test example embodiment 1-15 provides
1, test sample
15 compounds and classical antitumor TOPO inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin) that the embodiment 1-embodiment 15 of take provides are test sample, totally 16 kinds, wherein 10-hydroxycamptothecine is control group, and embodiment 1-15 sample is experimental group;
MTT is Sigma company product; The RPMI-1640 nutrient solution is GIBCO company product; Other reagent of using are domestic analytical reagent;
JEG-3 Chinese hamster ovary (CHO) cell, human leukemia cell (HL60) and murine leukemia cell (L1210) are all bought the Shanghai cell bank from the Chinese Academy of Sciences.
2, measuring method
The concrete steps of measuring method are:
(1) at first above-mentioned 16 kinds of test samples are used respectively dimethyl sulfoxide (DMSO) (DMSO) to dissolve, be mixed with 1.0 * 10
-2μ molL
-1the storing solution of concentration, the RPMI-1640 nutrient solution of the calf serum that is 10% with mass percent concentration afterwards is diluted to storing solution the working fluid with 5 concentration gradients by 10 times of dilution methods;
(2) carry out respectively two groups of experiments, first group of experiment to as if Chinese hamster ovary (CHO) cell of logarithmic phase, second group of experiment to as if human leukemia cell (HL60) and the murine leukemia cell (L1210) of logarithmic phase;
First group of experiment: the Chinese hamster ovary in the vegetative period of taking the logarithm (CHO) cell, be inoculated in 96 orifice plates with 5000, every hole cell, cultivate overnight after, add respectively the working fluid with 5 concentration gradients, discard substratum after 48 hours, every hole adds 1gL
-1blue (MTT) solution 100 μ L of bromination tetrazole, then continue to cultivate abandoning supernatant after 4 hours, and every hole adds the DMSO of 150 μ L, vibrates gently 30 minutes, measures afterwards absorbancy (OD) value at 570nm wavelength place by microplate reader;
Second group of experiment: the human leukemia cell in the vegetative period of taking the logarithm (HL60) and murine leukemia cell (L1210), be inoculated in 96 orifice plates with 7000, every hole cell, add respectively subsequently the working fluid with 5 concentration gradients, after 48 hours, every hole adds 5gL
-1mTT solution 10 μ L, continue cultivation and add sodium lauryl sulphate (SDS) water culture that 100 μ L mass percent concentrations are 10% to spend the night after 4 hours, then by microplate reader, at 570nm wavelength place, measures the OD value;
(3) calculate the inhibiting rate of the test sample of different concns to cancer cells by formula shown in following,
Inhibition of cancer cell rate=(1-experimental group OD value/control group OD value) * 100%, then do linear regression with the logarithmic value inhibition of cancer cell rate corresponding to each concentration of each concentration of test sample, obtain the docs-effect equation, from gained docs-effect Equation for Calculating, go out the half-inhibition concentration (IC of each test sample to the experiment cancer cells
50); Each data replicate(determination) three times, ask its mean value, the results are shown in Table shown in 1.
Anti-tumor activity (the IC of each test sample of table 1
50)
As can be seen from Table 1, the compound that embodiment 1-embodiment 15 provides has in vitro cytotoxic effect to the experimental leukemia JEG-3.General way according to drug development is first to carry out conventional antitumor in-vitro screening, then study targetedly, so compound of the present invention has strong anti-tumor activity, can be by with the acceptable sour salify of human body or be mixed with antitumor drug with pharmaceutical carrier.
Claims (7)
1. a levo-fluoroquinolone C 3 bisazole methyl sulfide, is characterized in that, chemical structural formula is as shown in formula I:
Wherein, X be selected from O, S ,-any in NH;
Ar is selected from any in phenyl, p-methoxyphenyl, p-methylphenyl, halogenophenyl, nitrophenyl.
2. levo-fluoroquinolone C 3 bisazole methyl sulfide according to claim 1, is characterized in that, Ar is selected from any in rubigan, p-nitrophenyl.
3. the preparation method of claim 1 or 2 a described levo-fluoroquinolone C 3 bisazole methyl sulfide, is characterized in that, comprises the following steps:
(1) levofloxacin is dissolved in the hydrazine hydrate that excessive mass percent concentration is 80%, then back flow reaction is 12～24 hours, makes the levofloxacin hydrazides, and the chemical structural formula of levofloxacin hydrazides is suc as formula shown in B;
(2) take the levofloxacin hydrazides makes compound shown in the general formula II as raw material;
(3) shown in compound shown in the general formula II and general formula III, compound carries out condensation under acidity or alkaline condition, make levo-fluoroquinolone C 3 bisazole methyl sulfide, the chemical structural formula of levo-fluoroquinolone C 3 bisazole methyl sulfide is as shown in formula I, and shown in its formula of II, the mol ratio of compound shown in compound and general formula III is: compound shown in the general formula II: compound=1:(1.2 shown in the general formula III～1.3);
4. the preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide according to claim 3, is characterized in that, in step (2), when the X in compound shown in the general formula II is O, the structural formula of compound shown in the general formula II is formula C:
The preparation method of compound shown in formula C is: first the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, and then drip dithiocarbonic anhydride in the ethanolic soln of potassium hydroxide, normal-temperature reaction is 3 hours afterwards, then reflux is dissolved the solid in reaction system fully, decompression and solvent recovery is to dry afterwards, add water in residuum, use the gac reflux decolour, filter, filtrate is adjusted to neutrality with hydrochloric acid, there is solid to separate out, the solid of separating out washes with water, drying obtains compound shown in formula C again, levofloxacin hydrazides wherein, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1:1.5:1.5.
5. the preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide according to claim 3, is characterized in that, and in step (2), the X in compound shown in the general formula II is-and during NH, the structural formula of compound shown in the general formula II is formula D:
The preparation method of compound shown in formula D is: the levofloxacin hydrazides is dissolved in the dilute hydrochloric acid that mass percent concentration is 6%, add potassium thiocyanate afterwards in described dilute hydrochloric acid, then back flow reaction is 12 hours, filter, the gained filter cake is dissolved in the aqueous sodium hydroxide solution that mass percent concentration is 8% again, then back flow reaction is 6 hours, use afterwards activated carbon decolorizing, filter, filtrate is adjusted to neutrality with hydrochloric acid, separate out solid, the solid of separating out washes with water, drying again, obtain compound shown in formula D, wherein the mol ratio of levofloxacin hydrazides and potassium thiocyanate is: levofloxacin hydrazides: potassium thiocyanate=1:1.5.
6. the preparation method of levo-fluoroquinolone C 3 bisazole methyl sulfide according to claim 3, is characterized in that, in step (2), when the X in compound shown in the general formula II is S, the structural formula of compound shown in the general formula II is formula E:
The preparation method of compound shown in formula E is: the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, be placed in afterwards ice bath, drip dithiocarbonic anhydride again in the ethanolic soln of potassium hydroxide, then normal-temperature reaction is 24 hours, filter, filter cake is through washing, dry, milled processed, join afterwards in the vitriol oil of 0～10 ℃, being stirred to solid materials in 0～10 ℃ dissolves fully, then rising to stirring at normal temperature spends the night, pour into afterwards in the ethanol of 0 ℃, fully stir, placement is spent the night, filter, the gained filter cake is soluble in water, activated carbon decolorizing, filter, filtrate is adjusted to neutrality, separate out solid, the solid of separating out washes with water, dry, obtain compound shown in formula E, levofloxacin hydrazides wherein, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1:1.5:1.5.
7. the application of the described levo-fluoroquinolone C 3 bisazole methyl sulfide of claim 1～2 any one in preparing antitumor drug.
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| CN104592252B (en) * | 2015-01-16 | 2016-08-24 | 河南大学 | A kind of piperazine quinolinone C-3 triazole sulfide ketone thiosemicarbazone derivative and its preparation method and application |
| CN104557974B (en) * | 2015-01-16 | 2016-08-24 | 河南大学 | A kind of chiral fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound and its preparation method and application |
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| CN109761999A (en) * | 2018-11-13 | 2019-05-17 | 河南大学 | The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives |
| CN109762005A (en) * | 2018-11-14 | 2019-05-17 | 河南大学 | The preparation and application of double-fluoquinolone thiadiazoles ureas Rufloxacin derivative |
| CN109678885A (en) * | 2018-11-14 | 2019-04-26 | 河南大学 | The preparation and application of double-fluoquinolone thiadiazoles ureas N- methyl gatifloxacin derivative |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070238720A1 (en) * | 2005-05-10 | 2007-10-11 | Hopkins Scott J | Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures |
| WO2008013987A2 (en) * | 2006-07-27 | 2008-01-31 | Prolexys Pharmaceuticals, Inc. | N-alkyl substituted piperazinylmethylquinazolinones and azepanylmethylquinazolinones |
| US20090069560A1 (en) * | 2004-12-31 | 2009-03-12 | Quimica Sintetica, S.A. | Process For Obtaining Levofloxacin Free From Salts |
| CN101643471A (en) * | 2009-08-24 | 2010-02-10 | 河南大学 | C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof |
| CN101648962A (en) * | 2009-08-28 | 2010-02-17 | 河南大学 | C3/C3 fluoroquinolone dipolymer derivative taking s-triazolo-[3,4-b][1,3,4] thiadiazole as connecting chain and preparation method and application thereof |
-
2011
- 2011-09-28 CN CN 201110296594 patent/CN102391287B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090069560A1 (en) * | 2004-12-31 | 2009-03-12 | Quimica Sintetica, S.A. | Process For Obtaining Levofloxacin Free From Salts |
| US20070238720A1 (en) * | 2005-05-10 | 2007-10-11 | Hopkins Scott J | Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures |
| WO2008013987A2 (en) * | 2006-07-27 | 2008-01-31 | Prolexys Pharmaceuticals, Inc. | N-alkyl substituted piperazinylmethylquinazolinones and azepanylmethylquinazolinones |
| CN101643471A (en) * | 2009-08-24 | 2010-02-10 | 河南大学 | C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof |
| CN101648962A (en) * | 2009-08-28 | 2010-02-17 | 河南大学 | C3/C3 fluoroquinolone dipolymer derivative taking s-triazolo-[3,4-b][1,3,4] thiadiazole as connecting chain and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 胡国强 等.水溶性稠杂环均三唑并噻二唑体系的合成及生物活性(II)：环丙氟喹诺酮哌嗪衍生物.《化学学报》.2008,第66卷(第19期),第2157-2162页. * |
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