CN106632323A - N-methylmoxifloxacin aldehyde thiosemicarbazone derivative, and preparation method and application thereof - Google Patents
N-methylmoxifloxacin aldehyde thiosemicarbazone derivative, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an N-methylmoxifloxacin aldehyde thiosemicarbazone derivative, and a preparation method and an application thereof. The N-methylmoxifloxacin aldehyde thiosemicarbazone derivative has a structure as shown in a general formula I in the specification. In the general formula I, R is selected from the group consisting of an H atom, or a hydrocarbyl group with 1 to 5 carbon atoms or a cyclopropyl group. The N-methylmoxifloxacin aldehyde thiosemicarbazone derivative provided by the invention realizes combination of three advantage pharmacophores like a fluoroquinolone skeleton, Schiff base imine and thiourea, thereby adding the antitumor activity of a novel compound, reducing the toxic and side effects on normal cells, and being able to be used as an antitumor active substance to develop an antitumor drug with a novel structure.
Description
Technical field
The invention belongs to new drug discovery and original new drug synthesis technical field, and in particular to a kind of N- methyl MOXIFLOXACIN aldehyde
Contracting base thiourea derivatives, also relate to a kind of preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives,
And its application in antineoplastic.
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 its with macromolecular or
Metal ion is also easy to produce complex or chelation and shows extensive pharmacologically active and receive much concern.However, building contracting amino
The aldehydes or ketones of thiocarbamide molecule mostly are 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 the action target spot-topoisomerase of FQNS be also antineoplastic important function target spot, can be resisted
Bacterium is active Transforming for antitumor activity.For this purpose, fluoquinolone C-3 converting carboxylate groups are formed into corresponding fluoquinolone C- for formoxyl
3 aldehyde, are then condensed with thiosemicarbazide, and then realize the split between chinoline backbone and thiosemicarbazones pharmacophore, to reaching
Activity superposition between different structure pharmacophore, therefrom finds the fluoquinolone candidate compound with antitumor activity.
The content of the invention
The present invention is directed to problems of the prior art, there is provided a kind of N- methyl MOXIFLOXACIN aldehyde (thiosemicarbazone) spreads out
Biology and preparation method thereof, with antineoplastic action and effect, can be applicable to the preparation of antineoplastic.
The technical solution adopted in the present invention is as follows：
N- methyl Moses's gatifloxacin aldehyde thiosemicarbazone derivatives, the general structure with such as following formula (I)：
Wherein, R is the alkyl of hydrogen atom or 1～5 carbon atom in Formulas I.
Above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives, the compound of specially following structure：
The preparation method of above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives, concrete preparation process includes：
(1) with the MOXIFLOXACIN shown in formula (II) as raw material, Jing methylation reactions are obtained the N- methyl shown in formula (III) not
Xisha star；
(2) the N- methyl MOXIFLOXACIN Jing hydrazinolysis reaction shown in formula (III) is obtained the N- methyl Moses shown in formula (IV)
Husky star hydrazides；Then N- methyl MOXIFLOXACIN hydrazides shown in formula (IV) is carried out the oxidation reaction of hydrazide group, it is post-treated to obtain
N- methyl MOXIFLOXACIN aldehyde shown in formula (V)；
(4) the N- methyl MOXIFLOXACIN aldehyde shown in formula (V) and the Methyl hydrazinecarbodithioate shown in formula (VI) are carried out
Condensation reaction, the post-treated N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates obtained shown in formula (VII)；
(4) the N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates shown in formula (VII) are entered with aminated compounds
Row nucleophilic substitution, the post-treated N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives obtained shown in formula (I)；Or by formula
(V) the N- methyl MOXIFLOXACIN aldehyde shown in carries out condensation reaction with thiosemicarbazides, and the post-treated N- methyl obtained shown in formula (I) is not
Xisha star aldehyde thiosemicarbazone derivatives；
The preparation method of above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives,
In step (2), the method for the oxidation reaction of hydrazide group is：By the N- methyl Enoxacin hydrazides shown in formula (IV) with
Potassium ferricyanide normal-temperature reaction in the mixed solvent of chloroform and concentrated ammonia liquor；
Wherein, the N- methyl MOXIFLOXACIN hydrazides shown in formula (IV) and the mol ratio of the potassium ferricyanide are 1:3.0～5.0.
The preparation method of above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives, in step (4), formula (VI) institute
The N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioate iodate hydrogen salts for showing are 1 with the mol ratio of aminated compounds:3.0～
10.0。
The preparation method of above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives, the aminated compounds is primary
Aminated compounds.
The preparation method of above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives, the primary amine compound is
Methylamine, ethamine, isopropylamine, cyclopropylamine, tert-butylamine, n-butylamine or n-amylamine.
Application of the above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives in antineoplastic is prepared.
Application of the above-mentioned N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives in antineoplastic is prepared, it is special
Levy and be, the antineoplastic is treatment cancer of pancreas, liver cancer or leukemic medicine.
Beneficial effects of the present invention are as follows：
Principle of hybridization of the N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives of the present invention based on pharmacophore, by fluorine
Efficient combination is carried out between the different pharmacophores of three kinds of quinolone, imines schiff bases and thiocarbamide etc., and then it is husky to devise N- methyl Moses
Star aldehyde contracting base thiosemicarbazides analog derivative, realizes the complementation of different structure pharmacophore and the superposition of activity, so as to reach increasing
The effect of effect toxicity reduction, can develop as the antineoplastic of brand new.
Specific embodiment
The preparation method of the N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives of the present invention, with formula (II) Suo Shi
MOXIFLOXACIN be prepared from for raw material,
Concrete preparation process is as follows：
1) methylation reaction that the MOXIFLOXACIN shown in formula (II) and formic acid and formaldehyde occur piperazine is obtained into formula (III) institute
Show N- methyl MOXIFLOXACINs；
Formula (III)
Concrete operation step is：MOXIFLOXACIN (50.0g, 125.0mmol) shown in formula (II) is dissolved in into 85% formic acid
(250mL) and 37% formaldehyde (20.0g, 200.0mmol) mixed solvent in, be stirred at reflux reaction 12 hours, reaction terminates
Afterwards, remove solvent under reduced pressure, add water (1000mL), with 30% sodium hydroxide solution pH to 7.0 is adjusted, place and separate out solid, filter collection
Solid, is dried, and is then 3 with volume ratio:The mixed solvent recrystallization of 2 absolute ethyl alcohol-DMF, obtains pale yellow crystals, structural formula
Such as formula (III), yield 68%, 207～209 DEG C of mp；
1H NMR(400MHz,CDCl3)δ:15.17(brs,1H,COOH),8.72(s,1H,1H,2-H),7.68(d,1H,
5-H), 4.06 (m, 1H, 1 "-H), 3.87～3.23 (m, 10H, 1 ', 3 ', 7 ', 9 '-H and OCH3),2.66(m,1H,6′-
H),2.26(s,3H,N-CH3), 1.75～the 1.82 (- H of the and of m, 4H, 4 ' 5 '), 1.23～0.86 (m, 4H, 2 " and 3 "-H)；
MS(m/z):Calcd.for C22H26FN3O4:415.47[M]+；Found:416[M+H]+。
2) be there is into hydrazinolysis reaction in the N- methyl MOXIFLOXACIN shown in formula (III) and hydrazine hydrate and N- first shown in formula (IV) is obtained
Base MOXIFLOXACIN hydrazides；
Concrete operation step is：By N- methyl MOXIFLOXACINs (20.0g, 48.0mmol) shown in formula (III) and 85% water
The mixed solvent back flow reaction of conjunction hydrazine (50mL) and absolute ethyl alcohol (100mL) 24 hours, placement is cooled to room temperature, and filter collects solid,
Gained solid is recrystallized with absolute ethyl alcohol, obtains yellow crystal, structural formula such as formula (IV), yield 58.2%, 186～188 DEG C of mp；
1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,CDCl3)δ:11.36(s,1H,CONH),8.75(s,
1H,1H,2-H),7.70(d,1H,5-H),4.07(m,1H,1″-H),4.56(s,2H,NH2), 3.86～3.21 (m, 10H, 1 ',
3′、7′、9′-H and OCH3),2.65(m,1H,6′-H),2.26(s,3H,N-CH3), 1.74～1.83 (and of m, 4H, 4 '
5 '-H), 1.22～0.85 (m, 4H, 2 " and 3 "-H)；
MS(m/z):Calcd.for C22H28FN5O3:429.50[M]+；Found:430[M+H]+。
3) by the N- methyl MOXIFLOXACIN hydrazides shown in formula (IV) and the potassium ferricyanide chloroform and concentrated ammonia liquor (concentrated ammonia liquor it is dense
Spend for 22%～25%, similarly hereinafter) mixed solvent in normal-temperature reaction 8～12 hours, separate organic layer, washed with saturated common salt
Wash, anhydrous sodium sulfate drying removes solvent under reduced pressure, the N- methyl MOXIFLOXACIN C-3 aldehyde crude intermediates shown in formula (V) be obtained,
It is directly used in the next step.
Concrete operation step is：N- methyl MOXIFLOXACIN hydrazides (10.0g, 23.0mmol) shown in formula (IV) is suspended in
In the mixed solvent of chloroform (200 milliliters) and concentrated ammonia liquor (20 milliliters), normal temperature be slowly added dropwise the potassium ferricyanide (38.0g,
Water (120 milliliters) solution 115.0mmol), stirring at normal temperature reacts 8～12 hours to raw material disappearance (TLC detections, VChloroform：VMethyl alcohol=
5:1) after, reaction terminates, organic layer is separated, uses saturated common salt water washing, anhydrous sodium sulfate drying to remove solvent under reduced pressure, obtain formula
(V) the N- methyl MOXIFLOXACIN C-3 aldehyde crude intermediates shown in, it is standby.
4) it is obtained shown in formula (VI) with dimethyl suflfate reaction after being condensed hydrazine hydrate and carbon disulfide in alkaline medium
Methyl hydrazinecarbodithioate intermediate, its concrete operation step refers to document (Hu Weixiao, etc. thiosemicarbazones chemical combination
The synthesis of thing and its research of active anticancer, SCI, 2001,22 (12)：Preparation method 2014-2017)；
5) N- methyl MOXIFLOXACIN C-3 aldehyde crude products (10.0g) shown in formula (V) is dissolved in absolute ethyl alcohol (150 milliliters), plus
Enter the Methyl hydrazinecarbodithioate (3.9g, 32.0mmol) shown in formula (VI), back flow reaction 10 hours, placement is cooled to room
Temperature, the solid that filter collection is produced, is dried, and is then 3 with volume ratio:The mixed solvent recrystallization of 1 methanol-chloroform, is obtained yellowish
Color is crystallized, i.e. N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioate, and shown in structural formula such as formula (VII), quality is
168～170 DEG C of 11.7g, mp；1H NMR (400MHz, DMSO-d6)：11.46 (s, 1H, CH=N), 8.78 (s, 1H, 1H, 2-
), H 8.46 (s, 1H, NH), 7.84 (d, 1H, 5-H), 4.08 (m, 1H, 1 "-H), 3.87～3.16 (m, 10H, 1 ', 3 ', 7 ', 9 '-
H and OCH3),2.63(m,1H,6′-H),2.24(s,3H,N-CH3), 1.70～the 1.85 (- H of the and of m, 4H, 4 ' 5 '), 2.05
(s,3H,SCH3), 1.18～0.87 (m, 4H, 2 " and 3 "-H)；MS(m/z):Calcd.for C22H28FN5O3:429.50[M
]+；Found:430[M+H]+。
5) by the N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates shown in formula (VII) and aminated compounds just
Carry out nucleophilic substitution in butanol, Jing processes to obtain N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives shown in formula (I)；
Or the N- methyl MOXIFLOXACIN C-3 aldehyde crude products shown in formula (V) and thiosemicarbazides are carried out into condensation reaction, Jing processes to obtain formula (I) institute
The N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives for showing；Concrete operation step is shown in embodiment part.
Step 5) in, solvent used may be selected methyl alcohol, ethanol, normal propyl alcohol, isopropanol and isobutyl in addition to n-butanol, also
At least one in alcohol, wherein it is preferred that n-butanol or ethanol.
Embodiment 1
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline
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：N- methyl MOXIFLOXACIN C-3 aldehyde crude products (1.0g) shown in formula (V) is dissolved in into nothing
Water-ethanol (20 milliliters), adds thiosemicarbazides (0.3g, 3.3mmol), back flow reaction 12 hours to filter and collect solid while hot,
Gained solid is washed successively 2 times with ethanol, distillation water washing 2 times, is dried, and is then 1 with volume ratio：:5 DMF- ethanol it is mixed
Bonding solvent is recrystallized, and obtains yellow crystal thing, structural formula such as formula (I-1), and quality is 0.68g, m.p.246～248 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.84 (s, 1H, 2-H), 8.45 (s, 1H,
NH),8.36(s,1H,NH2),8.33(s,1H,NH2), 7.84 (d, 1H, 5-H), 4.08 (m, 1H, 1 "-H), 3.91～3.16 (m,
10H,1′、3′、7′、9′-H and OCH3),2.66(m,1H,6′-H),2.33(s,3H,N-CH3), 1.75～1.86 (m, 4H,
- the H of 4 ' and 5 '), 1.22～0.96 (m, 4H, 2 " and 3 "-H)；MS(m/z):Calcd.for C23H29FN6O2S:472.59
[M]+；Found:473[M+H]+。
Embodiment 2
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- methylamino thiocarbamides (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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioates
1.0g (2.33mmol) is dissolved in anhydrous normal butyl alcohol (25 milliliters), addition methylamine (0.72g, 23.0mmol), back flow reaction 12h,
Placement is cooled to room temperature, and the solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, and distillation water washing 2 times is dried, so
It is afterwards 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-2), quality
For 0.50g, m.p.215～217 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.82 (s, 1H, 2-H), 8.43 (s, 1H,
), NH 8.36 (s, 1H, NH), 4.07 (m, 1H, 1 "-H), 3.87～3.03 (m, 13H, 1 ', 3 ', 7 ', 9 '-H, CH3and OCH3),
2.65 (m,1H,6′-H),2.33(s,3H,N-CH3), 1.88～the 1.70 (- H of the and of m, 4H, 4 ' 5 '), 1.21～0.93 (m,
4H,2″and3″-H)；
MS(m/z):Calcd.for C24H31FN6O2S:486.62[M]+；Found:487[M+H]+。
Embodiment 3
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- ethylamino thiocarbamides (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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioates
1.0g (2.33mmol) is dissolved in anhydrous normal butyl alcohol (25 milliliters), adds ethamine (1.05g, 23mmol), back flow reaction 12h to put
Put and be cooled to room temperature, the solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, distillation water washing 2 times is dried, then
It is 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-3), and quality is
0.56g, m.p.212～214 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.82 (s, 1H, 2-H), 8.43 (s, 1H,
), NH 8.33 (s, 1H, NH), 4.07 (m, 1H, 1 "-H), 3.88～3.03 (m, 12H, 1 ', 3 ', 7 ', 9 '-H, CH2and OCH3),
2.65(m,1H,6′-H),2.33(s,3H,N-CH3), 1.78～1.66 (m, 7H, 4 ', 5 '-H and CH3), 1.22～0.88
(m,4H,2″and3″-H)；
MS(m/z):Calcd.for C25H33FN6O2S:500.64[M]+；Found:501[M+H]+。
Embodiment 4
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- isopropylamino thiocarbamides (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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioates
1.0g (2.33mmol) is dissolved in anhydrous normal butyl alcohol (25 milliliters), adds isopropylamine (1.18g, 20.0mmol), back flow reaction
12h, placement is cooled to room temperature, and the solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, and distillation water washing 2 times is done
It is dry, it is then 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-
4), quality is 0.62g, m.p.217～219 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.82 (s, 1H, 2-H), 8.46 (s, 1H,
), NH 8.35 (s, 1H, NH), 4.08 (m, 1H, 1 "-H), 3.91～3.06 (m, 11H, 1 ', 3 ', 7 ', 9 '-H, CH and
OCH3),2.67(m,1H,6′-H),2.33(s,3H,N-CH3), 1.82～the 1.68 (- H of the and of m, 4H, 4 ' 5 '), 1.27～0.90
(m,10H,2″、3″-H and2×CH3)；
MS(m/z):Calcd.for C26H35FN6O2S:514.67[M]+；Found:515[M+H]+。
Embodiment 5
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- cyclopropylamino thiocarbamides (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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate iodine
Change hydrogen salt 1.0g (1.60mmol) to be dissolved in anhydrous normal butyl alcohol (25 milliliters), add cyclopropylamine (0.92g, 16.0mmol), backflow
Reaction 12h, placement is cooled to room temperature, and the solid that filter collection is produced, gained is washed successively 2 times with ethanol, and distillation water washing 2 times is done
It is dry, it is then 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-
5), quality is 0.57g, m.p.234～236 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.47 (s, 1H, CH=N), 8.85 (s, 1H, 2-H), 8.53 (s, 1H,
), NH 8.44 (s, 1H, NH), 4.11 (m, 1H, 1 "-H), 3.93～3.08 (m, 11H, 1 ', 3 ', 7 ', 9 '-H, CH and
OCH3),2.68(m,1H,6′-H),2.34(s,3H,N-CH3), 1.84～the 1.73 (- H of the and of m, 4H, 4 ' 5 '), 1.26～0.81
(m,8H,2″、3″-H andCH2CH2)；
MS(m/z):Calcd.for C26H33FN6O2S:512.65[M]+；Found:513[M+H]+。
Embodiment 6
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracts 4 tert-butylamino thiocarbamides (I-6), and 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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioates
1.0g (2.33mmol) is dissolved in anhydrous normal butyl alcohol (25 milliliters), adds tert-butylamine (1.17g, 16.0mmol), back flow reaction
10h, placement is cooled to room temperature.The solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, distillation water washing 2 times, is done
It is dry, it is then 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-
6), quality is 0.62g, m.p.223～225 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.46 (s, 1H, CH=N), 8.83 (s, 1H, 2-H), 8.48 (s, 1H,
), NH 8.40 (s, 1H, NH), 4.10 (m, 1H, 1 "-H), 3.92～3.08 (m, 10H, 1 ', 3 ', 7 ', 9 '-H and OCH3),
2.67(m,1H,6′-H),2.33(s,3H,N-CH3), 1.87～the 1.72 (- H of the and of m, 4H, 4 ' 5 '), 1.55 (s, 9H, 3 ×
CH3), 1.25～0.88 (m, 4H, 2 " and 3 "-H)；
MS(m/z):Calcd.for C27H37FN6O2S:528.70[M]+；Found:529[M+H]+。
Embodiment 7
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- n-butylamino thiocarbamides (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 (VII) the fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S,
6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioates
1.0g (2.33mmol) is dissolved in anhydrous normal butyl alcohol (25 milliliters), adds n-butylamine (1.10g, 15.0mmol), back flow reaction
10h, placement is cooled to room temperature, and the solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, and distillation water washing 2 times is done
It is dry, it is then 1 with volume ratio:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-
7), quality is 0.55g, 214～216 DEG C of m.p.；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.82 (s, 1H, 2-H), 8.46 (s, 1H,
), NH 8.35 (s, 1H, NH), 4.10 (m, 1H, 1 "-H), 3.90～3.07 (m, 12H, 1 ', 3 ', 7 ', 9 '-H, CH2and OCH3),
2.66(m,1H,6′-H),2.33(s,3H,N-CH3), 1.87～the 1.68 (- H of the and of m, 4H, 4 ' 5 '), 1.35～0.68 (m,
11H,2″、3″-Hand CH2CH2CH3)；
MS(m/z):Calcd.for C27H37FN6O2S:528.70[M]+；Found:529[M+H]+。
Embodiment 8
The fluoro- 8- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -2,8- diazabicyclos [4.3.0]-nonane -8- bases-quinoline
Quinoline -4 (1H) -one -3- aldehyde contracting 4- pentylamines 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- methoxyl groups -7- of 1- cyclopropyl -6- [(1S, 6S) -
2,8- diazabicyclos [4.3.0]-nonane -8- bases]-quinoline -4 (1H) -one -3- aldehyde contracting Methyl hydrazinecarbodithioate 1.0g
(2.23mmol) in being dissolved in anhydrous normal butyl alcohol (25 milliliters), n-amylamine (1.04g, 12.0mmol), back flow reaction 8h is added to place
Room temperature is cooled to, the solid that filter collection is produced, gained solid is washed successively 2 times with ethanol, distillation water washing 2 times is dried, Ran Houyong
Volume ratio is 1:The mixed solvent recrystallization of 5 DMF- ethanol, obtains pale yellow crystals thing, structural formula such as formula (I-8), and quality is
0.52g, m.p.202～204 DEG C；
1H NMR (400MHz, DMSO-d6)δ:11.45 (s, 1H, CH=N), 8.82 (s, 1H, 2-H), 8.45 (s, 1H,
), NH 8.33 (s, 1H, NH), 4.09 (m, 1H, 1 "-H), 3.87～3.06 (m, 12H, 1 ', 3 ', 7 ', 9 '-H, CH2and OCH3),
2.66(m,1H,6′-H),2.33(s,3H,N-CH3), 1.88～the 1.68 (- H of the and of m, 4H, 4 ' 5 '), 1.25～0.66 (m,
13H,2″、3″-Hand CH2CH2CH2CH3)；
MS(m/z):Calcd.for C28H39FN6O2S:542.72[M]+；Found:543[M+H]+。
Test example
First, the anti tumor activity in vitro of the N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided
Determine
1st, test sample
With the N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided, and classical antitumor TOPO
Inhibitor 10-hydroxycamptothecine (HC) and MOXIFLOXACIN sand star (MX) are test sample, and totally 10 kinds, wherein HC and MX is control
Group, embodiment 1-8 sample is experimental group；
It is thin that experiment JEG-3 is respectively human liver cancer Hep-3B cell, 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 adopts African green monkey kidney cell (VERO cells), buys growth Science and Technology Ltd. logical in Shanghai.
2nd, assay method
Assay method is concretely comprised the following steps：
(1) above-mentioned 10 kinds of test samples are dissolved respectively with dimethyl sulfoxide (DMSO) (DMSO) 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.) by storing solution be 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 cell, human pancreas cancer Panc-1 cells and human leukemia HL60 cells and
VERO cell lines, with 6000, every hole cell 96 orifice plates are inoculated in, be subsequently 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 mean value is sought in each data parallel determination three times；
(3) inhibiting rate of the test sample of variable concentrations to cancer cell 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)
As it can be seen from table 1 the compound that embodiment 1-8 is provided is notable to the GIA of 3 kinds of experiment cancer cells
The activity of parent compound MOXIFLOXACIN (MX) is better than, it is right when especially the substituent R in Formulas I is compared with small-substituent or cyclopropyl
The growth activity of human pancreas cancer Panc-1 cells is quite or better than the antitumor activity of 10-hydroxycamptothecine.It is more meaningful,
The compound that embodiment 1-8 is provided shows relatively low toxicity to normal VERO cells, shows to tumour cell with stronger
It is selective, the potentiality with druggability and further carry out the value of new drug research.General way according to drug development is first
Carry out conventional antitumor in-vitro screening, then targetedly studied, therefore, in view of the compound of the present invention have it is strong
Antitumor activity and relatively low toxicity, can be mixed with antineoplastic by acid acceptable with human body into salt or with pharmaceutical carrier
Thing.
It should be noted last that：Above-described embodiment is merely to illustrate and unrestricted technical scheme, any right
Equivalent and the modification without departing from spirit and scope of the invention or local replacement that the present invention is carried out, it all should cover at this
Within bright protective scope of the claims.
Claims (9)
1.N- methyl Moses's gatifloxacin aldehyde thiosemicarbazone derivatives, it is characterised in that the structure with such as following formula (I) is led to
Formula：
Wherein, R is the alkyl of hydrogen atom or 1～5 carbon atom in Formulas I.
2. N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 1, it is characterised in that specially
The compound of following structure：
3. the preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 1 and 2, it is special
Levy and be, concrete preparation process includes：
(1) with the MOXIFLOXACIN shown in formula (II) as raw material, it is husky that Jing methylation reactions are obtained the N- methyl Moses shown in formula (III)
Star；
(2) the N- methyl MOXIFLOXACIN Jing hydrazinolysis reaction shown in formula (III) is obtained the N- methyl MOXIFLOXACINs shown in formula (IV)
Hydrazides；Then N- methyl MOXIFLOXACIN hydrazides shown in formula (IV) is carried out the oxidation reaction of hydrazide group, it is post-treated to obtain formula (V)
Shown N- methyl MOXIFLOXACIN aldehyde；
(3) the N- methyl MOXIFLOXACIN aldehyde shown in formula (V) and the Methyl hydrazinecarbodithioate shown in formula (VI) are condensed
Reaction, the post-treated N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates obtained shown in formula (VII)；
(4) the N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates shown in formula (VII) and aminated compounds are carried out into parent
Core substitution reaction, the post-treated N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives obtained shown in formula (I)；Or by formula (V)
Shown N- methyl MOXIFLOXACIN aldehyde carries out condensation reaction, the post-treated N- methyl Moses obtained shown in formula (I) with thiosemicarbazides
Husky star aldehyde thiosemicarbazone derivatives；
4. the preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 3, its feature
It is,
In step (2), the method for the oxidation reaction of hydrazide group is：By the N- methyl Enoxacin hydrazides shown in formula (IV) and iron cyanogen
Change potassium normal-temperature reaction in the mixed solvent of chloroform and concentrated ammonia liquor；
Wherein, the N- methyl MOXIFLOXACIN hydrazides shown in formula (IV) and the mol ratio of the potassium ferricyanide are 1:3.0～5.0.
5. the preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 3, its feature
It is, in step (4), the N- methyl MOXIFLOXACIN aldehyde contracting Methyl hydrazinecarbodithioates and aminated compounds shown in formula (VI)
Mol ratio is 1:3.0～10.0.
6. the preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 5, its feature
It is that the aminated compounds is primary amine compound.
7. the preparation method of N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 6, its feature
It is that the primary amine compound is methylamine, ethamine, isopropylamine, cyclopropylamine, tert-butylamine, n-butylamine or n-amylamine.
8. the N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives described in claim 1 or 2 are in antineoplastic is prepared
Application.
9. N- methyl MOXIFLOXACIN aldehyde thiosemicarbazone derivatives according to claim 8 are in antineoplastic is prepared
Application, it is characterised in that the antineoplastic is treatment cancer of pancreas, liver cancer or leukemic medicine.
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