CN106831823A - A kind of Rufloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application - Google Patents
A kind of Rufloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application Download PDFInfo
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- 0 CN(CC1)CCN1C(C(C1C2=C3)SCCN1C=C(C=NNC(NC*)=S)C2=O)=C3F Chemical compound CN(CC1)CCN1C(C(C1C2=C3)SCCN1C=C(C=NNC(NC*)=S)C2=O)=C3F 0.000 description 5
- LEEWHKPPAPAVDY-SDNWHVSQSA-N C/C(/CCNC(N)=S)=C\C1=CN(CCSc2c(c(F)c3)N4CCN(C)CC4)c2c3C1=O Chemical compound C/C(/CCNC(N)=S)=C\C1=CN(CCSc2c(c(F)c3)N4CCN(C)CC4)c2c3C1=O LEEWHKPPAPAVDY-SDNWHVSQSA-N 0.000 description 1
- IXTZOCFXAROXAN-LGJNPRDNSA-N CCCN(C)CCNc(c(F)c1)c2SCCN(C=C3/C=N/NC(C)NC4CC4)c2c1C3=O Chemical compound CCCN(C)CCNc(c(F)c1)c2SCCN(C=C3/C=N/NC(C)NC4CC4)c2c1C3=O IXTZOCFXAROXAN-LGJNPRDNSA-N 0.000 description 1
- XLKQVBOZPXQMIJ-UHFFFAOYSA-O CN(CC1)CCN1c(c(F)c1)c2SCCN(C=C3C=[NH2+])c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2SCCN(C=C3C=[NH2+])c2c1C3=O XLKQVBOZPXQMIJ-UHFFFAOYSA-O 0.000 description 1
- HRRQVVNZENCVRA-UHFFFAOYSA-N NC(NC1CC1)=S Chemical compound NC(NC1CC1)=S HRRQVVNZENCVRA-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems
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Abstract
The invention discloses Rufloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application, the general structure with such as following formula I：
Description
Technical field
Found and original new drug synthesis technical field the invention belongs to novel drugs, and in particular to Rufloxacin aldehyde contracting amino sulphur
Carbamide derivative, also relates to the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives, and it is in antineoplastic
Application in thing.
Background technology
New drug innovation originates from the discovery of primer, and the split structure primer molecule for being based on advantage pharmacophore skeleton is
Most economical and effective strategy.The thiosemicarbazone derivatives built by aldehydes or ketones and thiosemicarbazide because of it with macromolecular or
Metal ion is also easy to produce complex or chelation and shows extensive pharmacological activity and receive much concern.However, building contracting amino
The aldehydes or ketones of thiocarbamide molecule are generally the aldehyde and ketone of common benzene class or heteroaromatic class, and to quinoline aldehyde, especially fluoro quinolinone
The (thiosemicarbazone) that aldehydes is formed has not yet to see report.On the other hand, quinoline advantage pharmacophore skeleton is not only important day
Right product alkaloid, such as the important feature unit of quinine and camptothecin, are also the pharmacophore bone of antibacterial FQNS
Frame.Meanwhile, FQNS is water-soluble because increasing it with the presence of hydrophilic piperazinyl, improves bioavilability.Especially
It is FQNS action target spot-topoisomerase be also antineoplastic important function target spot, can be resisted
It is antitumor activity that bacterium is active Transforming.Therefore, by fluoquinolone C-3 converting carboxylate groups for formoxyl is formed corresponding fluoquinolone C-
3 aldehyde, are then condensed with thiosemicarbazides or substituted thiosemicarbazides, and then realize the split of quinoline and thiosemicarbazones pharmacophore,
To reach the activity superposition between different pharmacophores, the fluoquinolone candidate compound with antitumor activity is therefrom found.
The content of the invention
The present invention be directed to problems of the prior art, there is provided Rufloxacin aldehyde (thiosemicarbazone) analog derivative and its
Preparation method, with antineoplastic action and effect, can be applied to the preparation of antineoplastic.
Rufloxacin aldehyde thiosemicarbazone derivatives, the general structure with such as following formula (I)：
In formula (I), R is hydrogen atom or 1~5 alkyl of carbon atom.
Above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, the compound of specially following structure：
The preparation method of above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, specific preparation process includes：
(1) Rufloxacin shown in formula (II) carries out the Rufloxacin shown in the prepared formula (III) of hydrazinolysis reaction as raw material
Hydrazides；
(2) the Rufloxacin hydrazides shown in formula (III) is carried out the oxidation reaction of hydrazide group, formula (IV) institute can be obtained through treatment
The Rufloxacin aldehyde for showing；
(3) the Rufloxacin aldehyde and then shown in formula (IV) is condensed with the Methyl hydrazinecarbodithioate shown in formula (V)
Reaction, the post-treated Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate obtained shown in (VI)；
(4) the Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI) is carried out into nucleophilic with aminated compounds to take
Generation reaction, through processing to obtain Rufloxacin aldehyde thiosemicarbazone derivatives shown in formula (I)；Or the reed fluorine shown in formula (IV) is husky
Star aldehyde carries out condensation reaction, the post-treated Rufloxacin aldehyde thiosemicarbazone derivatives obtained shown in formula (I) with thiosemicarbazides；
The preparation method of above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, in step (2), the oxidation of hydrazide group is anti-
The method answered is：Rufloxacin hydrazides shown in formula (III) and the potassium ferricyanide is normal in the mixed solvent of chloroform and concentrated ammonia liquor
Temperature reaction；
Wherein, the Rufloxacin hydrazides shown in formula (III) and the mol ratio of the potassium ferricyanide are 1:3.0~5.0.
The preparation method of above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, in step (3), shown in the formula (V)
The mol ratio of Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate and aminated compounds be 1:3.0~10.0.
The preparation method of above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, the aminated compounds is primary amine class
Compound.
The preparation method of above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives, the primary amine compound be methylamine,
Ethamine, isopropylamine, cyclopropylamine, tert-butylamine, n-butylamine or n-amylamine.
Application of the above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives in antineoplastic is prepared.
Application of the above-mentioned Rufloxacin aldehyde thiosemicarbazone derivatives in antineoplastic is prepared, it is described antitumor
Medicine is the medicine for treating cancer of pancreas, liver cancer or leukaemia.
Beneficial effects of the present invention are as follows：
Rufloxacin aldehyde thiosemicarbazone derivatives of the present invention are based on the principle of hybridization of pharmacophore, by three ring fluorine quinolines
The different pharmacophores of three kinds of promise ketone, imines schiff bases and thiocarbamide etc. carry out efficient combination, have devised Rufloxacin aldehyde contracting amino sulphur
Carbamide derivative, realizes complementary and activity the superposition of different structure pharmacophore, so as to reach the effect of synergy toxicity reduction, can
Developed as the antineoplastic of brand new.
Specific embodiment
The preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives of the present invention, it is husky with the reed fluorine shown in formula (II)
Star (Rufloxacin) is prepared from for raw material,
Specific preparation process is as follows：
1) Rufloxacin shown in formula (II) and hydrazine hydrate are carried out into the Rufloxacin shown in the prepared formula (III) of hydrazinolysis reaction
Hydrazides；
Concrete operation step is：Rufloxacin (20.0g, 55.0mmol) and 85% hydrazine hydrate (50mL) and absolute ethyl alcohol
(100mL)
Mixed solvent back flow reaction 24 hours, placement is cooled to room temperature, filter collection solid, gained solid absolute ethyl alcohol weight
Crystallization, obtains yellow crystal, structural formula such as formula (III), yield 87%, 224~226 DEG C of mp；
1H NMR(400MHz,CDCl3)δ:11.35(s,1H,CONH),8.93(s,1H,2-H),7.84(d,1H,5-H),
4.68(t,2H,SCH2),4.55(s,2H,NH2), 3.43~3.14 (m, 10H, NCH2 and piperazine-H),2.32(s,
3H,N-CH3)；
MS(m/z):Calcd.for C17H20FN5O2S:377.44[M]+；Found:378[M+H]+。
2) by the Rufloxacin hydrazides shown in formula (III) and the potassium ferricyanide, in chloroform and concentrated ammonia liquor, (concentration of concentrated ammonia liquor is
Normal-temperature reaction 8~12 hours, separates organic layer in mixed solvent 22%~25%, similarly hereinafter), uses saturated common salt water washing, nothing
Aqueous sodium persulfate is dried, and removes solvent under reduced pressure, and the Rufloxacin C-3 aldehyde crude intermediates shown in formula (IV) are obtained, and is directly used in down
Step reaction；
Concrete operation step is：Rufloxacin hydrazides (10.0g, 27.0mmol) shown in formula (III) is suspended in chloroform
In the mixed solvent of (200 milliliters) and concentrated ammonia liquor (20 milliliters), normal temperature is slowly added dropwise the potassium ferricyanide (38.0g, 115.0mmol)
Water (120 milliliters) solution, stirring at normal temperature is reacted 8~12 hours to raw material disappearance (TLC detections, VChloroform：VMethyl alcohol=5:1), reaction knot
Shu Hou, separates organic layer, uses saturated common salt water washing, anhydrous sodium sulfate drying to remove solvent under reduced pressure, obtains the reed shown in formula (IV)
Flucloxacillin C-3 aldehyde crude products are standby.
3) with the hydrazine shown in the prepared formula (V) of dimethyl suflfate reaction after hydrazine hydrate is condensed with carbon disulfide in alkaline medium
Base dithiocarbonic acid methyl ester intermediate；Concrete operation step refers to document (Hu Weixiao, etc. the conjunction of thiosemicarbazones compound
Into and its active anticancer research, SCI, 2001,22 (12)：Preparation method 2014-2017)；
4) Rufloxacin C-3 aldehyde crude product (10.0g) shown in formula (IV) is dissolved in absolute ethyl alcohol (150 milliliters), adds formula
(V) Methyl hydrazinecarbodithioate (4.0g, 33.0mmol) shown in, back flow reaction 10 hours, placement is cooled to room temperature, filter collection
The solid of generation, dries, and is then 3 with volume ratio:The mixed solvent recrystallization of 1 methanol-chloroform, obtains pale yellow crystals, ties
Structure formula such as formula (VI) is shown, i.e. Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate, yield 75.3%, m.p.216~218 DEG C.
1H NMR (400MHz, DMSO-d6)：11.45 (s, 1H, CH=N), 8.87 (1H, s, 2-H), 8.43 (s, 1H, NH),
7.86 (d, 1H, 5-H), 4.72 (t, 2H, SCH2), 3.44~3.13 (m, 10H, NCH2 and piperazine-H),2.33(s,
3H,N-CH3),1.88(s,3H,SCH3)；
MS(m/z)：Calcd.for C20H24FN5O2S2：451.61[M]+；Found：452[M+H]+。
4) Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI) is entered with aminated compounds in n-butanol
Row nucleophilic substitution, through processing to obtain Rufloxacin aldehyde thiosemicarbazone derivatives shown in formula (I)；Or by formula (IV) Suo Shi
Rufloxacin C-3 aldehyde crude product and thiosemicarbazides carry out condensation reaction, through processing to obtain reed fluorine shown in formula (I) after question response is complete
Husky star aldehyde thiosemicarbazone derivatives；
Step 4) in, solvent for use may be selected in methyl alcohol, ethanol, normal propyl alcohol, isopropanol and isobutanol in addition to n-butanol, also
At least one, wherein it is preferred that n-butanol.
Embodiment 1
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde thiosemicarbazones
(I-1), its chemical structural formula is：
R i.e. in Formulas I is H atom.
The preparation method of the compound is：Rufloxacin C-3 aldehyde crude product (1.0g) is dissolved in absolute ethyl alcohol (20 shown in formula (IV)
Milliliter), thiosemicarbazides (0.5g, 5.5mmol) is added, back flow reaction 12 hours filters and collects solid while hot, and gained solid makes
Washed with ethanol 2 times, distillation water washing 2 times is dried, be then 5 with volume ratio:The mixed solvent recrystallization of 3 DMF- ethanol,
Pale yellow crystals thing is obtained, structural formula such as formula (I-1), quality is 0.64g, m.p.254~256 DEG C.
1H NMR (400MHz, DMSO-d6)δ:11.46 (s, 1H, CH=N), 8.86 (s, 1H, 2-H), 8.45 (s, 1H,
NH),8.37(s,1H,NH2),8.35(s,1H,NH2), 7.86 (d, 1H, 5-H), 4.68 (t, 2H, SCH2), 3.43~3.15 (m,
10H,NCH2 and piperazine-H),2.33(s,3H,N-CH3)；
MS(m/z)：Calcd.for C18H21FN6OS2：420.53[M]+；Found：421[M+H]+。
Embodiment 2
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- methylamino sulphur
Urea (I-2), its chemical structural formula is：
R i.e. in Formulas I is methyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, methylamine (0.68g, 22.0mmol), back flow reaction 12h are added, placement is cooled to room temperature, the solid that filter collection is produced, gained
Solid is washed 2 times with ethanol successively, distillation water washing 2 times, is dried, and is then 1 with volume ratio:The mixing of 3 DMF- ethanol is molten
Agent is recrystallized, and obtains pale yellow crystals thing, and structural formula such as formula (I-2), quality is 0.56g, m.p.243~245 DEG C.
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.85 (s, 1H, 2-H), 8.42 (s, 1H,
NH), 8.33 (s, 1H, NH), 7.84 (d, 1H, 5-H), 4.67 (t, 2H, SCH2), 3.45~3.07 (m, 13H, NCH2 and
piperazine-H and CH3),2.33(s,3H,N-CH3)；
MS(m/z)：Calcd.for C19H23FN6OS2：434.56[M]+；Found：435[M+H]+。
Embodiment 3
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- ethylamino sulphur
Urea (I-3), its chemical structural formula is：
R i.e. in Formulas I is ethyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, ethamine (1.00g, 22.0mmol), back flow reaction 12h are added, placement is cooled to room temperature, the solid that filter collection is produced, gained
Solid is washed 2 times with ethanol successively, distillation water washing 2 times, is dried, and is then 1 with volume ratio:3 DMF- alcohol mixed solvents
Recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-2), quality is 0.51g, m.p.234~236 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.86 (s, 1H, 2-H), 8.40 (s, 1H,
NH), 8.31 (s, 1H, NH), 7.85 (d, 1H, 5-H), 4.66 (t, 2H, SCH2), 3.62~3.07 (m, 12H, 2 × NCH2 and
piperazine-H),2.33(s,3H,N-CH3),1.68(t,3H,CH3)；
MS(m/z)：Calcd.for C20H25FN6OS2：448.59[M]+；Found：449[M+H]+。
Embodiment 4
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- isopropylaminos
Thiocarbamide (I-4), its chemical structural formula is：
R i.e. in Formulas I is isopropyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, isopropylamine (1.00g, 17.0mmol), back flow reaction 12h are added, placement is cooled to room temperature, the solid that filter collection is produced, institute
Obtain solid to be washed with ethanol 2 times successively, distillation water washing 2 times is dried, be then 1 with volume ratio:The mixing of 3 DMF- ethanol
Solvent recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-3), quality is 0.57g, m.p.226~228 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.86 (s, 1H, 2-H), 8.38 (s, 1H,
NH), 8.31 (s, 1H, NH), 7.85 (d, 1H, 5-H), 4.66 (t, 2H, SCH2), 3.38~3.06 (m, 11H, NCH2 and
piperazine-H and CH),2.33(s,3H,N-CH3),1.26(m,6H,2×CH3)；
MS(m/z)：Calcd.for C21H27FN6OS2：462.62[M]+；Found：463[M+H]+。
Embodiment 5
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- cyclopropylaminos
Thiocarbamide (I-5), its chemical structural formula is：
R i.e. in Formulas I is cyclopropyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, cyclopropylamine (0.97g, 17.0mmol), back flow reaction 12h are added, placement is cooled to room temperature, the solid that filter collection is produced, institute
Obtain solid to be washed with ethanol 2 times successively, distillation water washing 2 times is dried, be then 1 with volume ratio:The mixing of 3 DMF- ethanol
Solvent recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-5), quality is 0.48g, m.p.235~237 DEG C.
1H NMR (400MHz, DMSO-d6)δ:11.47 (s, 1H, CH=N), 8.87 (s, 1H, 2-H), 8.44 (s, 1H,
NH), 8.35 (s, 1H, NH), 7.87 (d, 1H, 5-H), 4.66 (t, 2H, SCH2), 4.34~3.06 (m, 11H, NCH2 and
piperazine-H and CH),2.33(s,3H,N-CH3), 1.15~0.78 (m, 4H, CH2CH2)；
MS(m/z)：Calcd.for C21H25FN6OS2：460.60[M]+；Found：461[M+H]+。
Embodiment 6
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- tert-butyl group ammonia
Base thiocarbamide (I-6), its chemical structural formula is：
R i.e. in Formulas I is the tert-butyl group.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, tert-butylamine (0.88g, 12.0mmol), back flow reaction 10h are added, placement is cooled to room temperature, the solid that filter collection is produced, institute
Obtain solid to be washed with ethanol 2 times successively, distillation water washing 2 times is dried, be then 1 with volume ratio:The mixing of 3 DMF- ethanol
Solvent recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-6), quality is 0.53g, m.p.221~223 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.87 (s, 1H, 2-H), 8.42 (s, 1H,
NH), 8.33 (s, 1H, NH), 7.86 (d, 1H, 5-H), 4.64 (t, 2H, SCH2), 3.44~3.05 (m, 10H, NCH2 and
piperazine-H),2.33(s,3H,N-CH3),1.54(s,9H,3×CH3)；
MS(m/z)：Calcd.for C22H29FN6OS2：476.64[M]+；Found：477[M+H]+。
Embodiment 7
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- normal-butyl ammonia
Base thiocarbamide (I-7), its chemical structural formula is：
R i.e. in Formulas I is normal-butyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, n-butylamine (0.73g, 10.0mmol), back flow reaction 10h are added, placement is cooled to room temperature, the solid that filter collection is produced, institute
Obtain solid to be washed with ethanol 2 times successively, distillation water washing 2 times is dried, be then 1 with volume ratio:The mixing of 3 DMF- ethanol
Solvent recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-7), quality is 0.60g, m.p.213~215 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.87 (s, 1H, 2-H), 8.40 (s, 1H,
NH), 8.33 (s, 1H, NH), 7.87 (d, 1H, 5-H), 4.64 (t, 2H, SCH2), 3.48~3.06 (m, 10H, NCH2 and
piperazine-H),2.33(s,3H,N-CH3), 1.26~0.70 (m, 7H, CH2CH2CH3)；
MS(m/z)：Calcd.for C22H29FN6OS2：476.64[M]+；Found：477[M+H]+。
Embodiment 8
The fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- aldehyde contracting 4- n-pentyl ammonia
Base thiocarbamide (I-8), its chemical structural formula is：
R i.e. in Formulas I is n-pentyl.
The preparation method of the compound is：By shown in formula (VI) the fluoro- 8,1- of 6- (sulphur ethyl) -7- (4- thyl-piperazins -
1- yls)-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g (2.21mmol) be dissolved in anhydrous normal butyl alcohol (25 milli
Rise) in, n-amylamine (0.74g, 8.5mmol), back flow reaction 10h are added, placement is cooled to room temperature, the solid that filter collection is produced, institute
Obtain solid to be washed with ethanol 2 times successively, distillation water washing 2 times is dried, be then 1 with volume ratio:The mixing of 3 DMF- ethanol
Solvent recrystallization, obtains pale yellow crystals thing, and structural formula such as formula (I-7), quality is 0.55g, m.p.205~207 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.86 (s, 1H, 2-H), 8.40 (s, 1H,
NH), 8.33 (s, 1H, NH), 7.88 (d, 1H, 5-H), 4.64 (t, 2H, SCH2), 3.44~3.06 (m, 10H, NCH2 and
piperazine-H),2.33(s,3H,N-CH3), 1.18~0.63 (m, 9H, CH2CH2CH2CH3)；
MS(m/z)：Calcd.for C23H31FN6OS2：490.67[M]+；Found：490.67[M+H]+。
Test example
First, the anti tumor activity in vitro of the Rufloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided is determined
1st, test sample
With the Rufloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided, and classical antitumor TOPO inhibitor
10-hydroxycamptothecine (HC) and Rufloxacin (RF) are test sample, and totally 10 kinds, wherein HC and RF is control group, embodiment 1-8
Sample is experimental group；
It is thin that experiment JEG-3 is respectively human liver cancer Hep-3B cells, human pancreas cancer Panc-1 cells and human leukemia HL60
Born of the same parents' strain is bought from Chinese Academy of Sciences's Shanghai cell bank.
Normal cell uses African green monkey kidney cell (VERO cells), buys and leads to growth Science and Technology Ltd. in Shanghai.
2nd, assay method
Assay method is concretely comprised the following steps：
(1) above-mentioned 10 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) (DMSO) respectively first, is configured to 1.0 × 10- 2mol·L-1The storing solution of concentration, afterwards with the RPMI-1640 nutrient solutions (purchase of the calf serum that mass percent concentration is 10%
From lark prestige Science and Technology Ltd.) storing solution is diluted to 5 concentration gradients (0.1,1.0,5.0,10.0,50.0, unit
It is a μm olL-1) working solution；
Take the logarithm growth period human liver cancer Hep-3B cells, human pancreas cancer Panc-1 cells and human leukemia HL60 cells and
VERO cell lines, 96 orifice plates are inoculated in 6000, every hole cell, be then separately added into above-mentioned 10 kinds of samples with 5 concentration
The working solution of gradient, culture adds 5gL per hole after 48 hours–1The μ L of MTT (tetrazolium bromide) solution 10, add after continuing to cultivate 4 hours
Enter lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10%, be further cultured for 24 hours, then use enzyme mark
Instrument determines respective absorbance (OD) value at 570nm wavelength, and its average value is sought in each data parallel determination three times；
(3) inhibiting rate of the test sample to cancer cell of various concentrations is calculated by following shown formula,
Inhibition of cancer cell rate=[(1- experimental group OD values)/control group OD values] × 100%,
Then linear regression is made to the corresponding inhibition of cancer cell rate of each concentration with the logarithm value of each concentration of test sample, is obtained
To docs-effect equation, each test sample is calculated to testing the half-inhibition concentration of cancer cell from gained docs-effect equation
(IC50), the results are shown in Table shown in 1.
Antitumor activity (the IC of each test sample of table 150)
The compound of embodiment 1-8 offers is can be seen that to 3 kinds from the initial in vitro antitumor activity screening result of table 1
The GIA for testing cancer cell is significantly stronger than the activity of parent compound Rufloxacin (RF), the especially substitution in Formulas I
When base R is compared with small-substituent or cyclopropyl, the activity to human pancreas cancer Panc-1 cells is anti-swollen equivalent to 10-hydroxycamptothecine
Tumor activity, its IC50Value has reached micro-molar concentration.More meaningful, the compound that embodiment 1-8 is provided is thin to normal VERO
Born of the same parents show relatively low toxicity, show that compound on tumor cell has a stronger selectivity, potentiality with druggability and new
The value of medicine exploitation.General way according to drug development is first to carry out conventional antitumor in-vitro screening, is then directed to
The research of property, therefore, in view of compound of the invention has strong antitumor activity and relatively low toxicity, can be by can with human body
The acid of receiving is mixed with antineoplastic into salt or with pharmaceutical carrier.
It should be noted last that：Above-described embodiment is merely to illustrate the technical scheme being not intended to limit the present invention, any right
Equivalent and do not depart from the modification of spirit and scope of the invention or locally replace that the present invention is carried out, it all should cover in this hair
Within bright protective scope of the claims.
Claims (9)
1. Rufloxacin aldehyde thiosemicarbazone derivatives, it is characterised in that the general structure with such as following formula (I)：
In formula (I), R is hydrogen atom or 1~5 alkyl of carbon atom.
2. Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 1, it is characterised in that specially following knot
The compound of structure：
3. the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 1 and 2, its feature exists
In specific preparation process includes：
(1) Rufloxacin shown in formula (II) carries out the Rufloxacin acyl shown in the prepared formula (III) of hydrazinolysis reaction as raw material
Hydrazine；
(2) the Rufloxacin hydrazides shown in formula (III) is carried out the oxidation reaction of hydrazide group, can be obtained shown in formula (IV) through treatment
Rufloxacin aldehyde；Then the Rufloxacin aldehyde shown in formula (IV) is condensed with the Methyl hydrazinecarbodithioate shown in formula (V)
Reaction, the post-treated Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate obtained shown in (VI)；
(3) that the Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI) is carried out into nucleophilic displacement of fluorine with aminated compounds is anti-
Should, through processing to obtain Rufloxacin aldehyde thiosemicarbazone derivatives shown in formula (I)；Or by the Rufloxacin aldehyde shown in formula (IV)
Condensation reaction, the post-treated Rufloxacin aldehyde thiosemicarbazone derivatives obtained shown in formula (I) are carried out with thiosemicarbazides；
4. the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 3, it is characterised in that step
Suddenly in (2), the method for the oxidation reaction of hydrazide group is：By the Rufloxacin hydrazides shown in formula (III) and the potassium ferricyanide in chloroform
With normal-temperature reaction in the mixed solvent of concentrated ammonia liquor；
Wherein, the Rufloxacin hydrazides shown in formula (III) and the mol ratio of the potassium ferricyanide are 1:3.0~5.0.
5. the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 3, it is characterised in that step
Suddenly in (3), the Rufloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in the formula (VI) is with the mol ratio of aminated compounds
1:3.0~10.0.
6. the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 5, it is characterised in that institute
Aminated compounds is stated for primary amine compound.
7. the preparation method of Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 5, it is characterised in that institute
Primary amine compound is stated for methylamine, ethamine, isopropylamine, cyclopropylamine, tert-butylamine, n-butylamine or n-amylamine.
8. application of the Rufloxacin aldehyde thiosemicarbazone derivatives in antineoplastic is prepared described in claim 1 or 2.
9. Rufloxacin aldehyde thiosemicarbazone derivatives according to claim 8 in antineoplastic is prepared should
With, it is characterised in that the antineoplastic is the medicine for treating cancer of pancreas, liver cancer or leukaemia.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020103170A1 (en) * | 2000-07-12 | 2002-08-01 | Turner Steven Ronald | Oxazinoquinolones useful for the treatment of viral infections |
| CN102827187A (en) * | 2012-07-18 | 2012-12-19 | 河南大学 | Fluoroquinolone acetal isoniazone, and preparation method and application thereof |
| CN104557974A (en) * | 2015-01-16 | 2015-04-29 | 河南大学 | Chiral fluoroquinolone C-3 s-triazole sulfide ketone thiosemicarbazone compounds as well as preparation method and application thereof |
| CN104592252A (en) * | 2015-01-16 | 2015-05-06 | 河南大学 | Oxazinoquinolinone C-3 sym-triazole sulfide ketone thiosemicarbazone derivative as well as preparation method and application thereof |
-
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- 2016-12-26 CN CN201611214426.2A patent/CN106831823B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020103170A1 (en) * | 2000-07-12 | 2002-08-01 | Turner Steven Ronald | Oxazinoquinolones useful for the treatment of viral infections |
| CN102827187A (en) * | 2012-07-18 | 2012-12-19 | 河南大学 | Fluoroquinolone acetal isoniazone, and preparation method and application thereof |
| CN104557974A (en) * | 2015-01-16 | 2015-04-29 | 河南大学 | Chiral fluoroquinolone C-3 s-triazole sulfide ketone thiosemicarbazone compounds as well as preparation method and application thereof |
| CN104592252A (en) * | 2015-01-16 | 2015-05-06 | 河南大学 | Oxazinoquinolinone C-3 sym-triazole sulfide ketone thiosemicarbazone derivative as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李清寒: "缩氨基硫脲类化合物的合成及生物活性研", 《西南民族大学学报•自然科学版》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276369A (en) * | 2021-10-26 | 2022-04-05 | 河南大学 | Isoleucinine analogs, preparation method and application of isoleucinine analogs from rufloxacin to isoleucinine analogs |
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