CN102443011B - Levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt, preparation method and application thereof - Google Patents
Levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt, preparation method and application thereof Download PDFInfo
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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
- OFDQYXADSXHDNN-KRWDZBQOSA-N C[C@@H]1N(C=C(c([nH]2)nnc2SCc2nnc(-c(cc3)ccc3OC)[o]2)C(c2cc(F)c3N4CC[N+](C)(C)CC4)=O)c2c3OC1 Chemical compound C[C@@H]1N(C=C(c([nH]2)nnc2SCc2nnc(-c(cc3)ccc3OC)[o]2)C(c2cc(F)c3N4CC[N+](C)(C)CC4)=O)c2c3OC1 OFDQYXADSXHDNN-KRWDZBQOSA-N 0.000 description 1
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Abstract
The invention relates to the technical field of medicines, in particular discloses a levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt, and further discloses a preparation method and application of the levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt in the pharmaceutical field simultaneously. The chemical structural formula of the levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt is represented by a general formula I: the general formula I is described in the specification. The levorotatory fluoroquinolone C3 diazole methyl sulfide quaternary ammonium salt provided by the invention has stronger in-vitro cytotoxicity effect on experimental leukemia cancer cell strains and stronger anti-tumor activity, and can be mixedly prepared into anti-tumor medicines with human body acceptable acidic salts or pharmaceutical carriers.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3, also relate to the preparation method of the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3 simultaneously and in the application of pharmacy field.
Background technology
Fluoroquinolone (FQ) is that be clinical antimicrobial drug that representative development come with Norxin (norfloxicin) eighties in last century.Have similar function based on its action target spot topoisomerase (TOPO) to Mammals TOPO, accordingly antibiotic FQ being converted into antitumor FQ is a new direction of studying at present.Though designed and synthesized structure and comprise antitumor FQ compounds such as two ring quinolones, three ring quinolones, Fourth Ring quinolones, chirality quinolone, flavonoid class, but at present these compounds have toxicity in varying degrees and active parallel, poor solubility causes bioavailability common problem (Wang Xiaotian etc. low, that easily needed to be resolved hurrily by metabolism inactivation etc. in vivo in the body, Chinese Pharmaceutical Journal, 2004,39,890).Therefore, seek new structural modification approach, find that new lead compound is present problem demanding prompt solution.Recent studies on is at present found, though fluoroquinolone C-3 carboxyl is necessary to anti-microbial activity, but be not necessity to anti-tumor activity, existing discovering 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 have strong anti-tumor activity.In addition, though azole compounds has a large amount of synthetic reports, do not appear in the newspapers as yet as the research of the isostere of levofloxacin C-3 carboxyl.
Summary of the invention
The object of the present invention is to provide the two azoles dimethyl sulfide quaternary ammonium salts of a kind of left-handed fluoroquinolone C3.
The present invention also aims to provide a kind of left-handed fluoroquinolone C3 preparation method of two azoles dimethyl sulfide quaternary ammonium salts.
The present invention also aims to provide a kind of left-handed fluoroquinolone C3 application of two azoles dimethyl sulfide quaternary ammonium salts.
In order to realize above purpose, the technical solution adopted in the present invention is: the two azoles dimethyl sulfide quaternary ammonium salts of a kind of left-handed fluoroquinolone C3, and its chemical structural formula is shown in general formula I:
General formula I,
Wherein, X be selected from O, S ,-among the NH any;
Ar is selected from phenyl, contains substituent phenyl, in the heteroaromatic alkyl any;
R is selected from (C
1-C
10) alkyl, (C
2-C
10) alkylene, (C
2-C
10) alkynes base, (C
3-C
10) in the aryl radical of cycloalkyl, replacement, the heteroaromatic alkyl of replacement any;
L is selected from any in halogen, high hydracid root, nitrate radical, sulfate radical, sulfur hydrogen anion, inferior sulfate radical, phosphate radical and the hydrogen phosphate.
Preferably, Ar is selected from any in phenyl, alkoxyl phenyl, alkyl phenyl, halogenophenyl, the nitrophenyl.
Further preferred, Ar is selected from any in phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, the p-nitrophenyl.
R is preferably (C
1-C
10) alkyl.Methyl more preferably.
L is preferably halogen.I more preferably.
A kind of preparation method of left-handed fluoroquinolone C3 azoles dimethyl sulfide quaternary ammonium salt may further comprise the steps:
(1) levofloxacin being dissolved in excessive mass percent concentration is that back flow reaction is 12～24 hours then, makes the levofloxacin hydrazides in 80% the hydrazine hydrate, and the chemical structural formula of levofloxacin hydrazides is suc as formula shown in the A;
(2) be that raw material makes compound shown in the general formula I I with the levofloxacin hydrazides;
(3) compound shown in compound and the general formula III carries out condensation shown in the general formula II under acidity or alkaline condition, make left-handed fluoroquinolone C3 azoles dimethyl sulfide, the chemical structural formula of left-handed fluoroquinolone C3 azoles dimethyl sulfide is shown in general formula I V, and wherein the mol ratio of compound shown in compound and the general formula III is shown in the general formula I I: compound shown in the general formula I I: compound shown in the general formula III=1: (1.2～1.3);
(4) left-handed fluoroquinolone C3 azoles dimethyl sulfide is dissolved in the anhydrous propanone, adds R-L then, reacted 1～10 hour, placement is spent the night, and filters, and the gained filter cake is left-handed fluoroquinolone C3 azoles dimethyl sulfide quaternary ammonium salt, and its chemical structural formula is shown in general formula I;
Formula A
General formula I I general formula III
General formula I V
General formula I;
Wherein, X be selected from O, S ,-among the NH any;
Ar is selected from phenyl, contains substituent phenyl, in the heteroaromatic alkyl any;
R is selected from (C
1-C
10) alkyl, (C
2-C
10) alkylene, (C
2-C
10) alkynes base, (C
3-C
10) in the aryl radical of cycloalkyl, replacement, the heteroaromatic alkyl of replacement any;
L is selected from any in halogen, high hydracid root, nitrate radical, sulfate radical, sulfur hydrogen anion, inferior sulfate radical, phosphate radical and the hydrogen phosphate.
Preferably, Ar is selected from any in phenyl, alkoxyl phenyl, alkyl phenyl, halogenophenyl, the nitrophenyl.
Further preferred, Ar is selected from any in phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, the p-nitrophenyl.
R is preferably (C
1-C
10) alkyl.Methyl more preferably.
L is preferably halogen.I more preferably.
Further, in step (2), when the X in the compound shown in the general formula I I was O, the structural formula of compound was formula B shown in the general formula I I:
Formula B,
The preparation method of compound shown in the formula B is: earlier the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, and then in the ethanolic soln of potassium hydroxide, drip dithiocarbonic anhydride, normal-temperature reaction is 3 hours afterwards, reflux is dissolved the solid in the reaction system fully then, decompression and solvent recovery is to doing afterwards, in residuum, add water, use the gac reflux decolour, filter, filtrate transfers to neutrality with hydrochloric acid, has solid to separate out, and the solid of separating out washes with water, drying gets compound shown in the formula C again, wherein the levofloxacin hydrazides, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1: 1.5: 1.5.
In the step (2), when the X in the compound shown in the general formula I I be-during NH, the structural formula of compound is formula C shown in the general formula I I:
Formula C,
The preparation method of compound shown in the formula C is: it is in 6% the dilute hydrochloric acid that the levofloxacin hydrazides is dissolved in mass percent concentration, in described dilute hydrochloric acid, add potassium thiocyanate afterwards, back flow reaction is 12 hours then, filter, it is in 8% the aqueous sodium hydroxide solution that the gained filter cake is dissolved in mass percent concentration again, back flow reaction is 6 hours then, use activated carbon decolorizing afterwards, filter, filtrate transfers to neutrality with hydrochloric acid, separates out solid, the solid of separating out washes with water, drying gets compound shown in the formula D again, and wherein the mol ratio of levofloxacin hydrazides and potassium thiocyanate is: the levofloxacin hydrazides: potassium thiocyanate=1: 1.5.
In the step (2), when the X in the compound shown in the general formula I I was S, the structural formula of compound shown in the general formula I I was formula D:
Formula D,
The preparation method of compound shown in the formula D is: the levofloxacin hydrazides is dissolved in the ethanolic soln of potassium hydroxide, place ice bath afterwards, in the ethanolic soln of potassium hydroxide, drip dithiocarbonic anhydride again, normal-temperature reaction is 24 hours then, filter, filter cake is through washing, dry, milled processed joins in 0～10 ℃ the vitriol oil afterwards, being stirred to solid materials in 0～10 ℃ dissolves fully, rise to stirring at normal temperature then and spend the night, pour into afterwards in 0 ℃ the ethanol, fully stir, placement is spent the night, filter, the gained filter cake is soluble in water, activated carbon decolorizing, filter, filtrate transfers to neutrality, separates out solid, and the solid of separating out washes with water, dry, get compound, wherein levofloxacin hydrazides shown in the formula E, the mol ratio of potassium hydroxide and dithiocarbonic anhydride is: levofloxacin hydrazides: potassium hydroxide: dithiocarbonic anhydride=1: 1.5: 1.5.
In the step (3), the preparation method of the two azoles dimethyl sulfides of left-handed fluoroquinolone C3 is:
It is 85%～95% aqueous ethanolic solution that compound shown in compound shown in the general formula I I and the general formula III is put into mass percent concentration, stirring and dissolving transfers to slightly acidic, and back flow reaction is 12～24 hours afterwards, evaporated under reduced pressure solvent then, the residuum water dissolution, activated carbon decolorizing filters, the filtrate adjust pH is to alkalescence, use chloroform extraction then, extraction liquid gets the two azoles dimethyl sulfides of left-handed fluoroquinolone C3 through washing, dry, concentrated;
Perhaps compound shown in the general formula I I is put into DMF, and then adding yellow soda ash, stirring at normal temperature 1 hour, add compound shown in the general formula III afterwards, be stirred to that compound dissolves fully shown in the general formula I I, pour into then in the water, use chloroform extraction, extraction liquid gets the two azoles dimethyl sulfides of left-handed fluoroquinolone C3 through washing, dry, concentrated.
The two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3 provided by the invention have stronger cell in vitro toxic action to the experimental leukemia JEG-3, have strong anti-tumor activity, can be by being mixed with antitumor drug with the acceptable sour salify of human body or with pharmaceutical carrier.
Embodiment
Below by specific embodiment technical scheme of the present invention is elaborated.
Embodiment 1-15 is the specific embodiment of the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3.
Embodiment 1
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 2
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 3
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 4
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 5
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 6
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 7
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 8
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 9
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 10
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 11
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 12
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 13
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 14
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Embodiment 15
(S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide, structural formula is:
Be the two azoles dimethyl sulfide quaternary ammonium salt preparation methods' of left-handed fluoroquinolone C3 specific embodiment below, at first prepare following compound.
(1) preparation levofloxacin hydrazides
The structural formula of levofloxacin hydrazides is formula A, and its preparation method is:
Formula A
Take by weighing the 57g levofloxacin, afterwards the levofloxacin that takes by weighing is put into the 100mL mass percent concentration and be 80% hydrazine hydrate, back flow reaction 18 hours, be cooled to room temperature, underpressure distillation is up to evaporate to dryness, and residuum obtains the levofloxacin hydrazides with 300mL dehydrated alcohol recrystallization.
(2) preparation (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl)-4 (1H)-quinolinones is formula B, its preparation method is:
Formula B
2.8g potassium hydroxide is dissolved in the 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, reflux to solid materials dissolves fully then, decompression and solvent recovery adds water 300mL to doing in residuum then, uses an amount of gac reflux decolour 1 hour afterwards, filter, remove gac, filtrate is with having solid to separate out hydrochloric acid adjust pH to 7, this moment, the solid of separating out washes with water, drying obtains (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl)-4 (1H)-quinolinone crude products are directly used in the next step.
(3) preparation (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones is formula C, its preparation method is:
Compound 1
Formula C
It is in 6% the dilute hydrochloric acid that 10g levofloxacin hydrazides (26.7mmol) is dissolved in the 200mL mass percent concentration, and then adding 4.0g potassium thiocyanate (40.0mmol), back flow reaction 12 hours, filter afterwards, filter cake is the crude product of compound 1, it is in 8% the aqueous sodium hydroxide solution that filter cake is dissolved in the 200mL mass percent concentration, refluxed 6 hours, and used an amount of gac reflux decolour 1 hour afterwards, filter, filtrate is used hydrochloric acid adjust pH to 7, separate out solid, the solid of separating out washes with water, drying, get (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinone crude products are directly used in the next step.
(4) preparation (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones is formula D, its preparation method is:
Compound 2
Formula D
2.8g potassium hydroxide is dissolved in the 200mL ethanol, make the ethanolic soln of potassium hydroxide, afterwards 10g levofloxacin hydrazides (26.7mmol) is dissolved in the ethanolic soln of potassium hydroxide, place afterwards and drip dithiocarbonic anhydride (3.0g under the ice bath, 40.0mmol), stirring at normal temperature 24 hours, filter, filter cake washs with anhydrous diethyl ether, dry compound 2 crude products that get, afterwards with compound 2 crude product grind into powders, slowly join the 100mL temperature and be in the cold vitriol oil about 5 ℃, insulated and stirred to solid materials dissolves fully under this temperature then, and then rise to stirring at normal temperature and spend the night, slowly pour the 500mL temperature afterwards into and be in 0 ℃ the ethanol, fully stir, placement is spent the night, and filters, the gained filter cake is (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 the 50mL water, adds an amount of gac reflux decolour 0.5 hour, filter, filtrate transfers to neutrality with ammoniacal liquor, separate out solid, the solid of separating out washes with water, drying, get (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone crude products are directly used in the next step.
Embodiment 16-30 is the two azoles dimethyl sulfide quaternary ammonium salt preparation methods' of left-handed fluoroquinolone C3 specific embodiment.
Embodiment 16
Present embodiment is the embodiment of the compound that provides of preparation embodiment 1, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl) to be suspended in the 20mL mass percent concentration be in 85% the aqueous ethanolic solution to-4 (1H)-quinolinones, drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then 2-chloromethyl-5-phenyl-1 of adding 1.5mmol, 3, the 4-oxadiazole, back flow reaction is 12 hours then, the evaporated under reduced pressure solvent, residuum adds water 30mL dissolving, with an amount of gac reflux decolour 1 hour, to filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product is used the dehydrated alcohol recrystallization again, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones; With (S)-8 of 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones are dissolved in the anhydrous propanone, add the methyl iodide of 0.1ml again, sealing oscillatory reaction 1 hour, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 2 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide products, yield 85%, m.p.182～184 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.54 (s, 1H, C
2-H), 8.22 (d, J=7.4Hz, 2H, Ph-H), 7.68～7.57 (m, 4H, C
5-H and Ph-H), 4.82 (s, 2H, SCH
2), 4.57～4.42 (m, 3H, OCH
2CHN), 3.57 (br s, 4H, 2 * piperizine-CH
2), 3.42,3.38 (2s, 6H,
+N (CH
3)
2), 2.74 (br s, 4H, 2 * piperizine-CH
2), 1.60 (d, J=6.6Hz, 3H, CH
3).
Embodiment 17
Present embodiment is the embodiment of the compound that provides of preparation embodiment 2, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl) to be suspended in the 20mL mass percent concentration be in 85% the aqueous ethanolic solution to-4 (1H)-quinolinones (1.2mmol), 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), back flow reaction is 12 hours then, the evaporated under reduced pressure solvent, residuum adds water 30mL dissolving, with an amount of gac reflux decolour 1 hour, to filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product is used the dehydrated alcohol recrystallization again, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.1ml again, sealing oscillatory reaction 10 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 2 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide products, yield 92%, m.p.187～189 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.62 (s, 1H, C
2-H), 8.27 (d, J=7.2Hz, 2H, Ph-H), 7.72 (d, J=7.4Hz, 2H, Ph-H), 7.56 (d, J=7.2Hz, 1H, C
5-H), 4.84 (s, 2H, SCH
2), 4.62～4.54 (m, 3H, OCH
2CHN), 3.89 (s, 3H, OCH
3), 3.56 (br s, 4H, 2 * piperizine-CH
2), 3.45,3.40 (2s, 6H,
+N (CH
3)
2), 2.74 (br s, 4H, 2 * piperizine-CH
2), 1.64 (d, J=6.6Hz, 3H, CH
3).
Embodiment 18
Present embodiment is the embodiment of the compound that provides of preparation embodiment 3, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl) to be suspended in the 20mL mass percent concentration be in 85% the aqueous ethanolic solution to-4 (1H)-quinolinones (1.2mmol), 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), back flow reaction is 12 hours then, the evaporated under reduced pressure solvent, residuum adds water 30mL dissolving, with an amount of gac reflux decolour 1 hour, to filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product is used the dehydrated alcohol recrystallization again, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.1ml again, sealing oscillatory reaction 5 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 2 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide products, yield 77%, m.p.166～167 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.67 (s, 1H, C
2-H), 8.14 (d, J=7.2Hz, 2H, Ph-H), 7.73 (d, J=7.2Hz, 2H, Ph-H), 7.64 (d, J=7.6,1H, C
5-H), 4.82 (s, 2H, SCH
2), 4.62～4.47 (m, 3H, OCH
2CHN), 3.51 (br s, 4H, 2 * piperizine-CH
2), 3.48,3.43 (2s, 6H,
+N (CH
3)
2), 2.74 (br s, 4H, 2 * piperizine-CH
2), 1.66 (d, J=6.4Hz, 3H, CH
3).
Embodiment 19
Present embodiment is the embodiment of the compound that provides of preparation embodiment 4, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl) to be suspended in the 20mL mass percent concentration be in 85% the aqueous ethanolic solution to-4 (1H)-quinolinones (1.2mmol), drip concentrated hydrochloric acid and be slightly acidic, heating for dissolving, and then adding 2-chloromethyl-5-rubigan-1,3,4-oxadiazole (1.5mmol), back flow reaction is 12 hours then, the evaporated under reduced pressure solvent, residuum adds water 30mL dissolving, with an amount of gac reflux decolour 1 hour, to filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product is used the dehydrated alcohol recrystallization again, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones, (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinones are dissolved in the anhydrous propanone, add the methyl iodide of 0.1ml again, sealing oscillatory reaction 5 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 2 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide products, yield 84%, m.p.187～189 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.56 (s, 1H, C
2-H), 8.14 (d, J=7.2Hz, 2H, Ph-H), 7.78 (d, J=7.4Hz, 2H, Ph-H), 7.64 (d, J=7.2Hz, 1H, C
5-H), 4.78 (s, 2H, SCH
2), 4.57～4.50 (m, 3H, OCH
2CHN), 3.53 (brs, 4H, 2 * piperizine-CH
2), 3.43,3.38 (2s, 6H,
+N (CH
3)
2), 2.72 (br s, 4H, 2 * piperizine-CH
2), 1.60 (d, J=6.6Hz, 3H, CH
3).
Embodiment 20
Present embodiment is the embodiment of the compound that provides of preparation embodiment 5, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-oxadiazole-2-yl) to be suspended in the 20mL mass percent concentration be in 85% the aqueous ethanolic solution to-4 (1H)-quinolinones (1.2mmol), 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), back flow reaction is 12 hours then, the evaporated under reduced pressure solvent, residuum adds water 30mL dissolving, with an amount of gac reflux decolour 1 hour, to filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product is used the dehydrated alcohol recrystallization again, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.1ml again, sealing oscillatory reaction 5 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 2 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-oxadiazole-2-yl]-4 (1H)-quinolinone iodide products, yield 91%, m.p.221～223 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.78 (s, 1H, C
2-H), 8.42 (d, J=7.2Hz, 2H, Ph-H), 7.84 (d, J=7.2Hz, 2H, Ph-H), 7.70 (d, J=7.6,1H, C
5-H), 4.88 (s, 2H, SCH
2), 4.62～4.51 (m, 3H, OCH
2CHN), 3.55 (br s, 4H, 2 * piperizine-CH
2), 3.47,3.40 (2s, 6H,
+N (CH
3)
2), 2.76 (br s, 4H, 2 * piperizine-CH
2), 1.64 (d, J=6.6Hz, 3H, CH
3).
Embodiment 21
Present embodiment is the embodiment of the compound that provides of preparation embodiment 6, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-2-chloromethyl-5-phenyl-1 of 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones (1.2mmol) and 0.3g, 3, it is in 95% the aqueous ethanolic solution, to drip the 1.0mL glacial acetic acid then that 4-oxadiazole (1.5mmol) is suspended in the 20mL mass percent concentration, makes reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent adds water 30mL dissolving in residuum, use an amount of gac reflux decolour 1 hour then, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product anhydrous propanone recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; With (S)-8 of 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinones are dissolved in the anhydrous propanone, add the methyl iodide of 0.2ml again, and back flow reaction is 6 hours then, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide products, yield 82%, m.p.205～207 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 13.2 (br s, 1H, NH), 8.62 (s, 1H, C
2-H), 8.18 (d, J=7.3Hz, 2H, Ph-H), 7.74～7.62 (m, 4H, C
5-H and Ph-H), 4.83 (s, 2H, SCH
2), 4.64～4.52 (m, 3H, OCH
2CHN), 3.55～3.46 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.78 (br s, 4H, 2 * piperizine-CH
2), 1.66 (d, J=6.6Hz, 3H, CH
3).
Embodiment 22
Present embodiment is the embodiment of the compound that provides of preparation embodiment 7, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-2-chloromethyl-5-p-methoxyphenyl-1 of 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones (1.2mmol) and 1.5mmol, 3, it is in 95% the aqueous ethanolic solution, to drip the 1.0mL glacial acetic acid then that the 4-oxadiazole is suspended in the 20mL mass percent concentration, makes reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent adds water 30mL dissolving in residuum, use an amount of gac reflux decolour 1 hour then, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product anhydrous propanone recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.2ml again, back flow reaction is 6 hours then, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide products, yield 82%, m.p.212～214 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 13.4 (br s, 1H, NH), 8.66 (s, 1H, C
2-H), 8.15 (d, J=7.2Hz, 2H, Ph-H), 7.72～7.53 (m, 3H, C
5-H and Ph-H), 4.82 (s, 2H, SCH
2), 4.67～4.52 (m, 3H, OCH
2CHN), 3.89 (s, 3H, OCH
3), 3.57～3.48 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.72 (br s, 4H, 2 * piperizine-CH
2), 1.65 (d, J=6.6Hz, 3H, CH
3).
Embodiment 23
Present embodiment is the embodiment of the compound that provides of preparation embodiment 8, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-2-chloromethyl-5-p-methylphenyl-1 of 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones (1.2mmol) and 1.5mmol, 3, it is in 95% the aqueous ethanolic solution, to drip the 1.0mL glacial acetic acid then that the 4-oxadiazole is suspended in the 20mL mass percent concentration, makes reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent adds water 30mL dissolving in residuum, use an amount of gac reflux decolour 1 hour then, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product anhydrous propanone recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.2ml again, back flow reaction is 6 hours then, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide products, yield 74%, m.p.194～196 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 13.1 (br s, 1H, NH), 8.58 (s, 1H, C
2-H), 8.11 (d, J=7.2Hz, 2H, Ph-H), 7.74～7.55 (m, 3H, C
5-H and Ph-H), 4.78 (s, 2H, SCH
2), 4.62～4.45 (m, 3H, OCH
2CHN), 3.38 (br s, 4H, 2 * piperizine-CH
2), 2.64 (br s, 4H, 2 * piperizine-CH
2), 3.54～3.46 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.77 (br s, 4H, 2 * piperizine-CH
2), 2.44 (s, 3H, Ph-CH
3), 1.66 (d, J=6.4Hz, 3H, CH
3).
Embodiment 24
Present embodiment is the embodiment of the compound that provides of preparation embodiment 9, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-2-chloromethyl-5-rubigan-1 of 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones (1.2mmol) and 1.5mmol, 3, it is in 95% the aqueous ethanolic solution, to drip the 1.0mL glacial acetic acid then that the 4-oxadiazole is suspended in the 20mL mass percent concentration, makes reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent adds water 30mL dissolving in residuum, use an amount of gac reflux decolour 1 hour then, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product anhydrous propanone recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.2ml again, back flow reaction is 6 hours then, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide products, yield 75%, m.p.192～194 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 13.4 (br s, 1H, NH), 8.57 (s, 1H, C
2-H), 8.22 (d, J=7.2Hz, 2H, Ph-H), 7.76 (d, J=7.2Hz, 2H, Ph-H), 7.57 (d, J=7.6,1H, C
5-H), 4.84 (s, 2H, SCH
2), 4.65～4.48 (m, 3H, OCH
2CHN), 3.57～3.48 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.73 (br s, 4H, 2 * piperizine-CH
2), 1.65 (d, J=6.4Hz, 3H, CH
3).
Embodiment 25
Present embodiment is the embodiment of the compound that provides of preparation embodiment 10, and its preparation method is:
With 0.5g (S)-8,1-[1,2-(oxygen propyl group)]-2-chloromethyl-5-p-nitrophenyl-1 of 6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-4H-1,2,4-triazole-3-yl)-4 (1H)-quinolinones (1.2mmol) and 1.5mmol, 3, it is in 95% the aqueous ethanolic solution, to drip the 1.0mL glacial acetic acid then that the 4-oxadiazole is suspended in the 20mL mass percent concentration, makes reaction system be slightly acidic, heating reflux reaction 24 hours, the evaporated under reduced pressure solvent adds water 30mL dissolving in residuum, use an amount of gac reflux decolour 1 hour then, filter, filtrate is alkalized with strong aqua, chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product anhydrous propanone recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in the anhydrous propanone, add the methyl iodide of 0.2ml again, back flow reaction is 6 hours then, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-and 4H-1,2,4-triazole-3-yl]-4 (1H)-quinolinone iodide products, yield 76%, m.p.236～238 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 13.6 (br s, 1H, NH), 8.82 (s, 1H, C
2-H), 8.33 (d, J=7.2Hz, 2H, Ph-H), 7.88 (d, J=7.2Hz, 2H, Ph-H), 7.72 (d, J=7.6,1H, C
5-H), 4.88 (s, 2H, SCH
2), 4.66～4.53 (m, 3H, OCH
2CHN), 3.58～3.50 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.82 (br s, 4H, 2 * piperizine-CH
2), 1.67 (d, J=6.4Hz, 3H, CH
3).
Embodiment 26
Present embodiment is the embodiment of the compound that provides of preparation embodiment 11, and its preparation method is:
With (S)-8 of 0.5g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved among the 10mL DMF (N, dinethylformamide), add 1.0g yellow soda ash again, make reaction system be weakly alkaline, stirring at normal temperature 1 hour adds 2-chloromethyl-5-phenyl-1 of 0.3g then, 3,4-oxadiazole (1.5mmol) is stirred to (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves are poured reaction solution in the 50mL water into, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product dehydrated alcohol recrystallization, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones; With (S)-8 of 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones are dissolved in anhydrous propanone, add the methyl iodide of 0.1ml again, seal oscillatory reaction then 2 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-phenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide products, yield 72%, m.p.204～206 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.68 (s, 1H, C
2-H), 8.22 (d, J=7.4Hz, 2H, Ph-H), 7.82～7.64 (m, 4H, C
5-H and Ph-H), 4.88 (s, 2H, SCH
2), 4.66～4.47 (m, 3H, OCH
2CHN), 3.63 (br s, 4H, 2 * piperizine-CH
2), 3.48,3.42 (2s, 6H,
+N (CH
3)
2), 2.76 (br s, 4H, 2 * piperizine-CH
2), 1.64 (d, J=6.6Hz, 3H, CH
3).
Embodiment 27
Present embodiment is the embodiment of the compound that provides of preparation embodiment 12, its preparation method is: with (S)-8 of 0.5g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 1.0g yellow soda ash again, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, 2-chloromethyl-5-the p-methoxyphenyl-1,3 that adds 1.5mmol then, the 4-oxadiazole, be stirred to (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in the 50mL water into chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product dehydrated alcohol recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in anhydrous propanone, add the methyl iodide of 0.1ml again, sealed oscillatory reaction then 2 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methoxyphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide products, yield 81%, m.p.215～217 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.78 (s, 1H, C
2-H), 8.35 (d, J=7.2Hz, 2H, Ph-H), 7.78 (d, J=7.4Hz, 2H, Ph-H), 7.64 (d, J=7.2Hz, 1H, C
5-H), 4.88 (s, 2H, SCH
2), 4.67～4.58 (m, 3H, OCH
2CHN), 3.96 (s, 3H, OCH
3), 3.62 (br s, 4H, 2 * piperizine-CH
2), 3.47,3.43 (2s, 6H,
+N (CH
3)
2), 2.78 (br s, 4H, 2 * piperizine-CH
2), 1.66 (d, J=6.6Hz, 3H, CH
3).
Embodiment 28
Present embodiment is the embodiment of the compound that provides of preparation embodiment 13, its preparation method is: with (S)-8 of 0.5g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 1.0g yellow soda ash again, make reaction system be weakly alkaline, stirring at normal temperature 1 hour, 2-chloromethyl-5-the p-methylphenyl-1,3 that adds 1.5mmol then, the 4-oxadiazole, be stirred to (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves, reaction solution is poured in the 50mL water into chloroform extraction, washing, anhydrous sodium sulfate drying, get crude product, crude product dehydrated alcohol recrystallization gets intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in anhydrous propanone, add the methyl iodide of 0.1ml again, sealed oscillatory reaction then 2 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-methylphenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide products, yield 62%, m.p.186～188 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.80 (s, 1H, C
2-H), 8.26 (d, J=7.2Hz, 2H, Ph-H), 7.84 (d, J=7.2Hz, 2H, Ph-H), 7.68 (d, J=7.6,1H, C
5-H), 4.87 (s, 2H, SCH
2), 4.65～4.53 (m, 3H, OCH
2CHN), 3.56 (br s, 4H, 2 * piperizine-CH
2), 3.54,3.47 (2s, 6H,
+N (CH
3)
2), 2.76 (br s, 4H, 2 * piperizine-CH
2), 1.72 (d, J=6.4Hz, 3H, CH
3).
Embodiment 29
Present embodiment is the embodiment of the compound that provides of preparation embodiment 14, and its preparation method is:
With (S)-8 of 0.5g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved among the 10mL DMF (N, dinethylformamide), add 1.0g yellow soda ash again, make reaction system be weakly alkaline, stirring at normal temperature 1 hour adds 2-chloromethyl-5-rubigan-1 of 1.5mmol then, 3, the 4-oxadiazole is stirred to (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves are poured reaction solution in the 50mL water into, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product dehydrated alcohol recrystallization, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinones are dissolved in anhydrous propanone, add the methyl iodide of 0.1ml again, sealed oscillatory reaction then 2 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-rubigan-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide products, yield 68%, m.p.212～214 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.64 (s, 1H, C
2-H), 8.18 (d, J=7.2Hz, 2H, Ph-H), 7.82 (d, J=7.4Hz, 2H, Ph-H), 7.68 (d, J=7.2Hz, 1H, C
5-H), 4.84 (s, 2H, SCH
2), 4.62～4.53 (m, 3H, OCH
2CHN), 3.57 (br s, 4H, 2 * piperizine-CH
2), 3.48,3.44 (2s, 6H,
+N (CH
3)
2), 2.76 (br s, 4H, 2 * piperizine-CH
2), 1.64 (d, J=6.6Hz, 3H, CH
3).
Embodiment 30
Present embodiment is the embodiment of the compound that provides of preparation embodiment 15, and its preparation method is:
With (S)-8 of 0.5g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinones (1.2mmol) are dissolved among the 10mL DMF (N, dinethylformamide), add 1.0g yellow soda ash again, make reaction system be weakly alkaline, stirring at normal temperature 1 hour adds 2-chloromethyl-5-p-nitrophenyl-1 of 1.5mmol then, 3, the 4-oxadiazole is stirred to (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4-methylpiperazine-1-yl)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl)-4 (1H)-quinolinone completely dissolves are poured reaction solution in the 50mL water into, chloroform extraction, washing, anhydrous sodium sulfate drying gets crude product, crude product dehydrated alcohol recrystallization, get intermediate product (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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; (S)-8 with 0.2g, 1-[1,2-(oxygen propyl group)]-6-fluoro-7-(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 are dissolved in anhydrous propanone, add the methyl iodide of 0.1ml again, sealed oscillatory reaction then 2 hours, place afterwards and spend the night, filter, the gained filter cake is yellow solid, with washing with acetone 3 times, namely obtain (S)-8,1-[1,2-(oxygen propyl group)]-6-fluoro-7-(4,4-lupetazin-1-yl)-3-[5-(5-p-nitrophenyl-1,3,4-oxadiazole-2-methylthio group)-1,3,4-thiadiazoles-2-yl]-4 (1H)-quinolinone iodide products, yield 81%, m.p.237～239 ℃
1H NMR (DMSO-d
6, 400MHz) δ: 8.86 (s, 1H, C
2-H), 8.51 (d, J=7.2Hz, 2H, Ph-H), 7.87 (d, J=7.2Hz, 2H, Ph-H), 7.76 (d, J=7.6,1H, C
5-H), 4.92 (s, 2H, SCH
2), 4.67～4.54 (m, 3H, OCH
2CHN), 3.58～3.45 (m, 10H,
+N (CH
3)
2And 2 * piperizine-CH
2), 2.83 (br s, 4H, 2 * piperizine-CH
2), 1.68 (d, J=6.6Hz, 3H, CH
3).
Test the determination of cytotoxic activity of the two azoles dimethyl sulfide quarternary ammonium salt compounds of left-handed fluoroquinolone C3 that routine embodiment 1-15 provides
1, for test agent
15 compounds and the classical antitumor TOPO inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin) that provide with embodiment 1-embodiment 15 serve as that totally 16 kinds, wherein 10-hydroxycamptothecine is control group for test agent, 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 homemade 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 supplies test agent to use dimethyl sulfoxide (DMSO) (DMSO) dissolving respectively with above-mentioned 16 kinds, be mixed with 1.0 * 10
-2μ molL
-1The storing solution of concentration is that the RPMI-1640 nutrient solution of 10% calf serum is diluted to storing solution the working fluid with 5 concentration gradients by 10 times of dilution methods with mass percent concentration afterwards;
(2) carry out two groups of experiments respectively, 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, with 5000 cell inoculations in every hole in 96 orifice plates, cultivate overnight after, add the working fluid with 5 concentration gradients respectively, discard substratum after 48 hours, every hole adds 1gL
-1Bromination tetrazole indigo plant (MTT) solution 100 μ L continue to cultivate abandoning supernatant after 4 hours then, and every hole adds the DMSO of 150 μ L, vibrates gently 30 minutes, measures absorbancy (OD) value at 570nm wavelength place with microplate reader afterwards;
Second group of experiment: the human leukemia cell in the vegetative period of taking the logarithm (HL60) and murine leukemia cell (L1210), in 96 orifice plates, add the working fluid with 5 concentration gradients with 7000 cell inoculations in every hole subsequently respectively, every hole adds 5gL after 48 hours
-1MTT solution 10 μ L continue to cultivate that to add 100 μ L mass percent concentrations after 4 hours be that 10% sodium lauryl sulphate (SDS) water culture is spent the night, and measure the OD value at 570nm wavelength place with microplate reader then;
(3) by formula shown in following calculate different concns for the inhibiting rate of test agent to cancer cells,
Cancer cells inhibiting rate=(1-experimental group OD value/control group OD value) * 100%, for the logarithmic value of each concentration of test agent the cancer cells inhibiting rate of each concentration correspondence is done linear regression then, obtain the docs-effect equation, go out each for the half-inhibition concentration (IC of test agent to the experiment cancer cells from gained docs-effect Equation for Calculating
50); Its mean value is asked in each data replicate(determination) three times, the results are shown in Table shown in 1.
Each anti-tumor activity (IC for test agent of table 1
50)
As can be seen from Table 1, the compound that embodiment 1-embodiment 15 provides has the cell in vitro cytotoxic activity to the experimental leukemia JEG-3, and part is better than control group.General way according to drug development is to carry out conventional antitumor in-vitro screening earlier, study targetedly then, so compound of the present invention has strong anti-tumor activity, can be by being mixed with antitumor drug with the acceptable sour salify of human body or with pharmaceutical carrier.
Claims (5)
1. two azoles dimethyl sulfide quaternary ammonium salts of a left-handed fluoroquinolone C3 is characterized in that chemical structural formula is shown in formula I:
Formula I,
Wherein, X be selected from O, S ,-among the NH any;
Ar is selected from any in phenyl, p-methoxyphenyl, p-methylphenyl, halogenophenyl, the nitrophenyl;
R is methyl;
L is selected from any in halogen, high hydracid root, nitrate radical, sulfate radical, sulfur hydrogen anion, inferior sulfate radical, phosphate radical and the hydrogen phosphate.
2. the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3 according to claim 1 is characterized in that Ar is selected from any in rubigan, the p-nitrophenyl.
3. the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3 according to claim 1 is characterized in that L is I.
4. the preparation method of the two azoles dimethyl sulfide quaternary ammonium salts of the described left-handed fluoroquinolone C3 of claim 1 is characterized in that, may further comprise the steps:
(1) levofloxacin being dissolved in excessive mass percent concentration is that back flow reaction is 12～24 hours then, makes the levofloxacin hydrazides in 80% the hydrazine hydrate, and the chemical structural formula of levofloxacin hydrazides is suc as formula shown in the A;
(2) be that raw material makes compound shown in the general formula II with the levofloxacin hydrazides;
(3) compound carries out condensation shown in compound shown in the general formula II and the general formula III under acidity or alkaline condition, make the two azoles dimethyl sulfides of left-handed fluoroquinolone C3, the chemical structural formula of the two azoles dimethyl sulfides of left-handed fluoroquinolone C3 is shown in the general formula IV, and the mol ratio of compound shown in compound and the general formula III is 1:1.2～1.3 shown in its formula of II;
(4) the two azoles dimethyl sulfides of left-handed fluoroquinolone C3 are dissolved in the anhydrous propanone, add R-L then, reacted 1～10 hour, placement is spent the night, and filters, and the gained filter cake is the two azoles dimethyl sulfide quaternary ammonium salts of left-handed fluoroquinolone C3, and its chemical structural formula is shown in formula I;
5. the application of the two azoles dimethyl sulfide quaternary ammonium salts of the described left-handed fluoroquinolone C3 of claim 1 in the preparation 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 |
| CN104628702B (en) * | 2015-01-29 | 2017-01-04 | 河南大学 | A kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound and its preparation method and application |
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