CN104628702B - A kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound and its preparation method and application - Google Patents
A kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention discloses a kind of ring the third fluoroquinolone C 3 triazole sulfide ketone (thiosemicarbazone) compound and its preparation method and application, use such as following formula I chemical structure of general formula: in formula Formulas I, R is at least one in H, ether, hydroxyl, methyl, halogeno-group and nitro.A kind of ring the third fluoroquinolone C 3 triazole sulfide ketone (thiosemicarbazone) compound of the present invention, achieve superposition or the complementation of structure of three kinds of different pharmacophore activity such as fluoroquinolone skeleton and triazole heterocycle and thiosemicarbazones etc., thus add the anti-tumor activity of noval chemical compound, reduce Normocellular toxic and side effects, can be as the antitumor drug of anti-tumor active substance exploitation brand new.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone contracting
Thiosemicarbazide compound, also relates to the system of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound
Preparation Method, and its application in preparing antitumor drug.
Background technology
Malignant tumor is the major disease threatening human life healthy, and the medicine of current clinical practice is led because of poor selectivity
Causing toxicity greatly, low to the therapeutic index of tumor, the antitumor drug therefore developing new structure is the most urgent.Based on antibacterial fluorine quinoline
The effect target topoisomerase topoisomerase corresponding with in mammalian body of promise ketone, can at sequence and the similarity of function
By the structural modification of fluoroquinolone, its antibacterial activity is converted into its anti-tumor activity.Meanwhile, though fluoroquinolone C-3 position carboxyl
It is so pharmacophore necessary to antibacterial activity, but is not the pharmacophore of anti-tumor activity, can be substituted by heterocycle isostere.With this
Meanwhile, in many heterocyclic compounds, triazole is the pharmacophore that a class is important, and its derivant is because having multiple pharmacologically active
Drug design receives much concern.Further, since (thiosemicarbazone) not only can produce important with many kinds of metal ions chelating
Pharmacological action, is often used as an important pharmacophore to build drug molecule skeleton, and its derivant is because having as disease-resistant simultaneously
The biological activity widely such as poison, antibacterium, antifungal, anti-tumor activity and cause the attention of pharmaceutical chemists.Especially
The antitumor action target spot of some heterocycle (thiosemicarbazone) compounds is also likely to be DNA topoisomerase II (TopoII),
Become the focus of antitumor drug research.
Summary of the invention
It is an object of the invention to provide a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound,
There is antineoplastic action and effect, a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) is provided simultaneously
The preparation method and application of compound.
In order to realize object above, the technical solution adopted in the present invention is: a kind of ring the third fluoroquinolone C-3 triazole sulfur
Ether ketone (thiosemicarbazone) compound, its chemical structural formula is as shown in logical formula (I):
Formula (I)
In formula (I), R is at least one in H, ether, hydroxyl, methyl, halogeno-group and nitro.
One ring of the present invention third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound, this compounds has
Body is the compound of following chemical constitution:
A kind of preparation method of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound of the present invention,
It is that raw material is prepared from the N-methyl ciprofloxacin shown in formula (II),
Formula (II) formula (III)
Concrete preparation process is as follows:
1) the N-methyl ciprofloxacin shown in formula (II) is prepared corresponding hydrazides (III), hydrazides (III) and sulfur through hydrazinolysis
Potassium cyanide condensation prepares C-3 amide groups thiourea (IV), and it occurs intramolecular cyclisation to C-3 in 5wt%NaOH aqueous solution
Triazole mercaptan (V), its Detailed operating procedures be referred to document (Yang Yong. quinolinones C-3 [1,3,4] triazole thioether and derivative
The synthesis of thing and antitumor activity, He'nan University's Master's thesis, 2011. the method described in).
Formula (IV) formula (V)
2) C-3 triazole mercaptan (V) of above-mentioned preparation and alpha-brominated 1-Phenylethanone. or alpha-brominated acetophenone derivs are anhydrous
Ethanol occur nucleophilic substitution prepare the C-3 triazole sulfide ketone compounds shown in formula (VI)；
Formula (VI)
Its Detailed operating procedures be referred to document (Yang Yong. fluorine promise ketone C-3 [1,3,4] triazole thioether and the conjunction of derivant
Become and antitumor activity, He'nan University's Master's thesis, 2011) described in method.
3) by the compound shown in formula (VI) and thiosemicarbazides back flow reaction 6～12 hours in glacial acetic acid, post-treated
And recrystallization, prepare the target compound shown in formula (I).
Formula (I)
As further improving, the C-3 triazole sulfide ketone derivant shown in formula (VI) and thiosemicarbazides mole be
1:1.0～1.5.
Described a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound is preparing antineoplastic agent
Application in thing.
Described antitumor drug is treatment bladder cancer, gastric cancer or pancreatic cancer drug.
The present invention a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound spelling based on pharmacophore
Close principle, three kinds of different pharmacophore such as fluoroquinolone, triazole heterocycle and thiosemicarbazones are effectively combined, it is achieved that structure
Complementation and pharmacophore activity superposition, reached the effect of potentiation toxicity reduction, can as brand new antitumor drug develop.
Detailed description of the invention
Below by specific embodiment, technical scheme is described in detail.
A kind of preparation method of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound of the present invention,
It is that raw material is prepared from the N-methyl ciprofloxacin shown in formula (II),
Formula (II) formula (III)
Concrete preparation process is as follows:
1) the N-methyl ciprofloxacin shown in formula (II) is prepared corresponding hydrazides (III), hydrazides (III) and sulfur through hydrazinolysis
Potassium cyanide condensation prepares C-3 amide groups thiourea (IV), and it occurs intramolecular cyclisation to C-3 in 5wt%NaOH aqueous solution
Triazole mercaptan (V), its Detailed operating procedures be referred to document (Yang Yong. quinolinones C-3 [1,3,4] triazole thioether and derivative
The synthesis of thing and antitumor activity, He'nan University's Master's thesis, 2011. the method described in).
Formula (IV)
Formula (V)
2) C-3 triazole mercaptan (V) of above-mentioned preparation and alpha-brominated 1-Phenylethanone. or alpha-brominated acetophenone derivs are anhydrous
Ethanol occur nucleophilic substitution prepare the C-3 triazole sulfide ketone compounds shown in formula (VI)；
Formula (VI)
Its Detailed operating procedures be referred to document (Yang Yong. fluorine promise ketone C-3 [1,3,4] triazole thioether and the conjunction of derivant
Become and antitumor activity, He'nan University's Master's thesis, 2011) described in method.
Embodiment 1
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-1-Phenylethanone. thiosemicarbazones (I-1), its chemical structural formula is:
I.e. R in Formulas I is hydrogen atom.
The preparation method of this compound is: take intermediate (S)-2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-1-Phenylethanone. (VI-1) (2.0g, 3.9mmol) is molten
In glacial acetic acid (20mL), add thiosemicarbazides (0.42g, 4.7mmol), mixture back flow reaction 6h.Remove solvent under reduced pressure, add
Water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate is adjusted to neutrality with strong aqua ammonia, and filter collection produces
Solid, washes, is dried, dehydrated alcohol recrystallization, obtains pale yellow crystals thing (I-1), productivity 64.3%, m.p.176～178 DEG C.1H NMR(400MHz,DMSO-d6) δ: 0.97～1.31 (m, 4H, cyclopropyl-CH2),2.26(s,3H,N-CH3),3.06-3.55
(m, 8H, piperazinyl-CH2), 3.68～3.72 (m, 1H, cyclopropyl-CH), 4.76 (s, 2H, SCH2),7.51-7.71(m,4H,
Ph-H and 8-H), 7.88-8.07 (m, 4H, NH, 5-H and Ph-H), 8.32,8.38 (2s, 2H, NH2),8.72(s,1H,2-H),
13.78(s,1H,triazole-NH)；MS(m/z):592[M+H]+, calculate (C28H30FN9OS2):591.74。
Embodiment 2
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(p-methoxyphenyl)-ethyl ketone thiosemicarbazones (I-2), its chemical structural formula is:
I.e. R in Formulas I is to methoxyl group.
The preparation method of this compound is: take intermediate (S)-2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(p-methoxyphenyl)-ethyl ketone (VI-2)
(2.0g, 3.6mmol) is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.37g, 4.0mmol), mixture back flow reaction
10h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-2), productivity
67.5%, m.p.180～182 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.05～1.33 (m, 4H, cyclopropyl-CH2),2.27
(s,3H,N-CH3), 3.12-3.57 (m, 8H, piperazinyl-CH2), 3.67～3.73 (m, 1H, cyclopropyl-CH), 3.87 (s, 3H,
OCH3),4.77(s,2H,SCH2), 7.56-7.78 (m, 3H, Ph-H and 8-H), 7.83-8.13 (m, 4H, NH, 5-H and Ph-H),
8.31,8.36(2s,2H,NH2),8.76(s,1H,2-H),13.77(s,1H,triazole-NH)；MS(m/z):622[M+H]+,
Calculate (C29H32FN9O2S2):621.76。
Embodiment 3
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(o-methoxyphenyl)-ethyl ketone thiosemicarbazones (I-3), its chemical structural formula is:
I.e. R in Formulas I is O-methoxy.
The preparation method of this compound is: take intermediate (S)-2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(o-methoxyphenyl)-ethyl ketone (VI-3)
(2.0g, 3.6mmol) is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.49g, 5.4mmol), mixture back flow reaction
12h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-3), productivity
46.2%, m.p.167～169 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.05～1.32 (m, 4H, cyclopropyl-CH2),2.25
(s,3H,N-CH3), 3.11～3.58 (m, 8H, piperazinyl-CH2), 3.66～3.74 (m, 1H, cyclopropyl-CH), 3.89 (s, 3H,
OCH3),4.76(s,2H,SCH2), 7.53～7.76 (m, 3H, Ph-H and 8-H), 7.85～8.18 (m, 4H, NH, 5-H and Ph-
H),8.32,8.35(2s,2H,NH2),8.77(s,1H,2-H),13.76(s,1H,triazole-NH)；MS(m/z):622[M+
H]+, calculate (C29H32FN9O2S2):621.76。
Embodiment 4
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(p-hydroxybenzene)-ethyl ketone thiosemicarbazones (I-4), its chemical structural formula is:
I.e. R in Formulas I is to hydroxyl.
The preparation method of this compound is: take intermediate (S)-2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(p-hydroxybenzene)-ethyl ketone (VI-4)
(2.0g, 3.7mmol) is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.34g, 3.7mmol), mixture back flow reaction
8h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-4), productivity
53.6%, m.p.183～185 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.07～1.36 (m, 4H, cyclopropyl-CH2),2.28
(s,3H,N-CH3), 3.17～3.63 (m, 8H, piperazinyl-CH2), 3.67～3.76 (m, 1H, cyclopropyl-CH), 4.78 (s, 2H,
SCH2), 7.58～7.76 (m, 4H, Ph-H, 8-H and NH), 7.87 (d, J=13.2Hz, 1H, 5-H), 8.15 (d, J=8.8Hz,
2H,Ph-H),8.35,8.41(2s,2H,NH2),8.81(s,1H,2-H),10.65(s,1H,OH),13.78(s,1H,
triazole-NH)；MS(m/z):608[M+H]+, calculate (C28H30FN9O2S2):607.74。
Embodiment 5
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(o-hydroxy-phenyl)-ethyl ketone thiosemicarbazones (I-5), its chemical structural formula is:
I.e. R in Formulas I is adjacent hydroxyl.
The preparation method of this compound is: take intermediate (S)-2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(o-hydroxy-phenyl)-ethyl ketone (VI-5)
(2.0g, 3.7mmol) is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.47g, 5.2mmol), mixture back flow reaction
10h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-5), productivity
48.7%, m.p.172～174 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.12～1.36 (m, 4H, cyclopropyl-CH2),2.27
(s,3H,N-CH3), 3.15～3.66 (m, 8H, piperazinyl-CH2), 3.65～3.74 (m, 1H, cyclopropyl-CH), 4.77 (s, 2H,
SCH2), 7.56～7.80 (m, 3H, Ph-H and 8-H), 7.86～8.18 (m, 4H, NH, 5-H and Ph-H), 8.33,8.37 (2s,
2H,NH2),8.78(s,1H,2-H),13.78(s,1H,triazole-NH)；MS(m/z):608[M+H]+, calculate
(C28H30FN9O2S2):607.74。
Embodiment 6
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(3,4-dioxymethylene-phenyl)-ethyl ketone thiosemicarbazones (I-6), its chemical structural formula is:
I.e. in Formulas I, R is 3,4-dioxymethylene atom.
The preparation method of above-claimed cpd is: 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4
(1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(3,4-dioxymethylene-phenyl)-ethyl ketone (VI-6) (2.0g,
3.6mmol) it is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.49g, 5.3mmol), mixture back flow reaction 12h.Decompression
Solvent is evaporated off, and add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.During filtrate is adjusted to strong aqua ammonia
Property, filter collection produce solid, washing, be dried, dehydrated alcohol recrystallization, pale yellow crystals thing (I-6), productivity 65.7%,
M.p.192～194 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.06～1.37 (m, 4H, cyclopropyl-CH2),2.26(s,3H,
N-CH3), 3.13～3.67 (m, 8H, piperazinyl-CH2), 3.66～3.78 (m, 1H, cyclopropyl-CH), 4.78 (s, 2H, SCH2),
6.26(s,2H,OCH2O), 7.63～7.82 (m, 3H, Ph-H and 8-H), 7.85～8.16 (s, 3H, NH, 5-H and Ph-H),
8.35,8.38(2s,2H,NH2),8.77(s,1H,2-H),13.77(s,1H,triazole-NH)；MS(m/z):636[M+H]+,
Calculate (C29H30FN9O3S2):635.75。
Embodiment 7
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(3,4-dimethoxy-phenylf)-ethyl ketone thiosemicarbazones (I-7), its chemical structural formula is:
I.e. R in Formulas I is 3,4-dimethoxy.
The preparation method of above-claimed cpd is: 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4
(1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(3,4-dimethoxy-phenylf)-ethyl ketone (VI-7) (2.0g,
3.5mmol) it is dissolved in glacial acetic acid (15mL), adds thiosemicarbazides (0.38g, 4.2mmol), mixture back flow reaction 12h.Decompression
Solvent is evaporated off, and add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.During filtrate is adjusted to strong aqua ammonia
Property, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-7), productivity 47.5%,
M.p.177～179 DEG C.1HNMR(400MHz,DMSO-d6) δ: 1.13～1.38 (m, 4H, cyclopropyl-CH2),2.27(s,3H,N-
CH3), 3.07～3.66 (m, 8H, piperazinyl-CH2), 3.62～3.75 (m, 1H, cyclopropyl-CH), 3.86,3.88 (2s, 9H, 3
×OCH3),4.77(s,2H,SCH2), 7.65-7.76 (m, 3H, Ph-H and 8-H), 7.84～8.15 (s, 3H, NH, 5-H and Ph-
H),8.34,8.36(2s,2H,NH2),8.78(s,1H,2-H),13.78(s,1H,triazole-NH)；MS(m/z):652[M+
H]+, calculate (C30H34FN9O3S2):651.79。
Embodiment 8
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(3-methoxyl group-4-hydroxy-pheny)-ethyl ketone thiosemicarbazones (I-8), its chemical structural formula is:
I.e. R in Formulas I is 3-methoxyl group-4-hydroxyl.
The preparation method of above-claimed cpd is: 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4
(1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(3-methoxyl group-4-hydroxy-pheny)-ethyl ketone (VI-8)
(2.0g, 3.5mmol) is dissolved in glacial acetic acid (15mL), adds thiosemicarbazides (0.42g, 4.6mmol), mixture back flow reaction
10h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-8), productivity
45.7%, m.p.181～183 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.10～1.37 (m, 4H, cyclopropyl-CH2),2.28
(s,3H,N-CH3), 3.13～3.68 (m, 8H, piperazinyl-CH2), 3.65～3.77 (m, 1H, cyclopropyl-CH), 3.88 (s, 3H,
OCH3),4.76(s,2H,SCH2), 7.66～7.78 (m, 3H, Ph-H and 8-H), 7.83～8.18 (m, 3H, NH, 5-H and Ph-
H),8.36,8.38(2s,2H,NH2),8.81(s,1H,2-H),10.57(s,1H,OH),13.77(s,1H,triazole-
NH)；MS(m/z):638[M+H]+, calculate (C29H32FN9O3S2):637.76。
Embodiment 9
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(to methylphenyl)-ethyl ketone thiosemicarbazones (I-9), its chemical structural formula is:
I.e. R in Formulas I is to methyl.
The preparation method of above-claimed cpd is: 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4
(1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(to methylphenyl)-ethyl ketone (VI-9) (2.0g, 3.8mmol)
It is dissolved in glacial acetic acid (15mL), adds thiosemicarbazides (0.41g, 4.6mmol), mixture back flow reaction 12h.Remove under reduced pressure molten
Agent, add water (30mL) dissolves, with adding the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate is adjusted to neutrality with strong aqua ammonia, filter
The solid that collection produces, washes, is dried, dehydrated alcohol recrystallization, obtains pale yellow crystals thing (I-9), productivity 45.0%, m.p.163
～165 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.05～1.33 (m, 4H, cyclopropyl-CH2),2.25,2.28(2s,6H,N-
CH3And CH3), 3.07-3.58 (m, 8H, piperazinyl-CH2), 3.62～3.76 (m, 1H, cyclopropyl-CH), 4.77 (s, 2H,
SCH2), 7.55～7.76 (m, 3H, Ph-H and 8-H), 7.83～8.03 (m, 4H, NH, 5-H and Ph-H), 8.32,8.36 (2s,
2H,NH2),8.78(s,1H,2-H),13.76(s,1H,triazole-NH)；MS(m/z):606[M+H]+, calculate
(C29H32FN9OS2):605.76。
Embodiment 10
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(to fluoro-phenyl)-ethyl ketone thiosemicarbazones (I-10), its chemical structural formula is:
I.e. R in Formulas I is to fluorine atom.
The preparation method of above-claimed cpd is: 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4
(1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(to fluoro-phenyl)-ethyl ketone (VI-10) (2.0g, 3.7mmol)
It is dissolved in glacial acetic acid (15mL), adds thiosemicarbazides (0.51g, 5.6mmol), mixture back flow reaction 10h.Remove under reduced pressure molten
Agent, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate is adjusted to neutrality, filter collection with strong aqua ammonia
The solid produced, washes, is dried, dehydrated alcohol recrystallization, obtains pale yellow crystals thing (I-10), productivity 53.8%, m.p.183～
185℃。1H NMR(400MHz,DMSO-d6) δ: 1.13～1.37 (m, 4H, cyclopropyl-CH2),2.26(s,3H,N-CH3),
3.15～3.64 (m, 8H, piperazinyl-CH2), 3.65～3.78 (m, 1H, cyclopropyl-CH), 4.82 (s, 2H, SCH2), 7.68～
7.78 (m, 3H, Ph-H and 8-H), 7.88～8.17 (m, 4H, NH, 5-H and Ph-H), 8.34,8.38 (2s, 2H, NH2),8.82
(s,1H,2-H),13.78(s,1H,triazole-NH)；MS(m/z):610[M+H]+, calculate (C28H29F2N9OS2):609.73。
Embodiment 11
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(to chloro-phenyl)-ethyl ketone thiosemicarbazones (I-11), its chemical structural formula is:
I.e. R in Formulas I is to chlorine atom.
The preparation method of above-claimed cpd is: take intermediate 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(to chloro-phenyl)-ethyl ketone (VI-11)
(2.0g, 3.6mmol) is dissolved in glacial acetic acid (15mL), adds thiosemicarbazides (0.40g, 4.3mmol), mixture back flow reaction
10h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-11), productivity
45.6%, m.p.168～170 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.10～1.35 (m, 4H, cyclopropyl-CH2),2.24
(s,3H,N-CH3), 3.13～3.58 (m, 8H, piperazinyl-CH2), 3.63～3.77 (m, 1H, cyclopropyl-CH), 4.78 (s, 2H,
SCH2), 7.65～7.76 (m, 3H, Ph-H and 8-H), 7.86～8.15 (m, 4H, NH, 5-H and Ph-H), 8.31,8.36 (2s,
2H,NH2),8.80(s,1H,2-H),13.77(s,1H,triazole-NH)；MS(m/z):626[M+H]+, calculate
(C28H29ClFN9OS2):626.16。
Embodiment 12
2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-quinoline-4 (1H)-one-3-base]-4H-[1,2,
4] triazole-3-sulfenyl }-1-(to nitro-phenyl)-ethyl ketone thiosemicarbazones (I-12), its chemical structural formula is:
I.e. R in Formulas I is to nitro.
The preparation method of above-claimed cpd is: take intermediate 2-{5-[the fluoro-7-of 1-cyclopropyl-6-(4-methyl piperazine-1-
Base)-quinoline-4 (1H)-one-3-base]-4H-[1,2,4] triazole-3-sulfenyl }-1-(to nitro-phenyl)-ethyl ketone (VI-12)
(2.0g, 3.6mmol) is dissolved in glacial acetic acid (20mL), adds thiosemicarbazides (0.39g, 4.3mmol), mixture back flow reaction
12h.Removing solvent under reduced pressure, add water (30mL) dissolves, and adds the activated carbon of 0.1g at 60 DEG C of stirring decolouring 1h.Filtrate strong aqua ammonia
It is adjusted to neutrality, the solid that filter collection produces, wash, be dried, dehydrated alcohol recrystallization, obtain pale yellow crystals thing (I-12), productivity
54.7%, m.p.192～194 DEG C.1H NMR(400MHz,DMSO-d6) δ: 1.15～1.42 (m, 4H, cyclopropyl-CH2),2.28
(s,3H,N-CH3), 3.17～3.66 (m, 8H, piperazinyl-CH2), 3.68～3.81 (m, 1H, cyclopropyl-CH), 4.83 (s, 2H,
SCH2), 7.76～8.13 (m, 5H, Ph-H, 8-H, NH, 5-H and Ph-H), 8.31～8.42 (m, 4H, NH2And Ph-H), 13.42
(s,1H,triazole-NH)；MS(m/z):637[M+H]+, calculate (C28H29FN10O3S2):636.73。
Test example
One, a kind of ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound that embodiment 1-12 provides
Anti tumor activity in vitro measure
1, test sample
12 new ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) chemical combination provided with embodiment 1-12
Thing and classical antitumor TOPO inhibitor 10-hydroxycamptothecine (HC) and parent compound ciprofloxacin (CF) are test sample,
Totally 14 kinds, wherein HC and CF is reference substance, and embodiment 1-12 sample is experimental group；
Experiment JEG-3 is respectively T24 transitional cell bladder carcinoma cell line, HGC823 stomach cancer cell, HGC27 stomach cancer cell, Panc-1 pancreas
Adenocarcinoma cell, Capan-1 pancreatic cancer cell, JEG-3 is all bought from Chinese Academy of Sciences's Shanghai cell bank.Normal cell uses
VERO African green monkey kidney cell, buys in upper Cacumen et folium clerodendri mandarinori (Clerodendron mandarinorum Diels) derivatives Science and Technology Ltd..
2, assay method
Concretely comprising the following steps of assay method:
(1) first above-mentioned 14 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) respectively, be configured to 10mmol L-1
The storing solution of concentration, the RPMI-1640 culture fluid with the calf serum that mass percent concentration is 10% is dilute by storing solution afterwards
It is interpreted into and there is 6 Concentraton gradient (1.0,10.0,20.0,30.0,40.0,50.0 μm ol L-1) working solution；
Take the logarithm the T24 transitional cell bladder carcinoma cell line of trophophase, HGC823 stomach cancer cell, HGC27 stomach cancer cell, Panc-1 cancer of pancreas
Cell and Capan-1 pancreatic cancer cell and VERO cell strain, be inoculated in 96 holes with every hole 100 μ L culture fluid containing 6000 cells
Plate, is separately added into the working solution with 6 Concentraton gradient of the 10 above-mentioned 14 kinds of samples of μ L subsequently, and is provided with without medicine blank control wells
(add the RPMI-1640 culture fluid of the 10 μ L calf serum that mass percent concentration is 10% containing DMSO, and the volume of DMSO
Of the total volume 1%), after 48 hours, every hole adds 5g L–1MTT (tetrazolium bromide) aqueous solution 10 μ L, continues to cultivate 4 hours
Rear addition 100 μ L mass percent concentration is sodium lauryl sulphate (SDS) hydroponics 24 hours of 10%, then uses enzyme mark
Instrument measures respective absorbance (OD) value at 570nm wavelength；
(3) test sample of the variable concentrations suppression ratio to cancerous cell is calculated by formula shown in following:
Inhibition of cancer cell rate=[(1-dosing holes OD value)/without medicine control wells OD value] × 100%,
Then with the logarithm value of each concentration of test sample, the inhibition of cancer cell rate that each concentration is corresponding is made linear regression,
To docs-effect equation, go out each test sample half-inhibition concentration to experiment cancerous cell from gained docs-effect Equation for Calculating
(IC50)；Each data parallel assay five times, seeks its meansigma methods, the results are shown in Table shown in 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 the inhibitory activity of 5 kinds of cancerous cell of experiment is significantly stronger than by the compound that embodiment 1-12 provides
The activity of the activity of parent compound ciprofloxacin, especially majority of compounds is better than or is equivalent to compare the work of hydroxycamptothecin
Property.More meaningful, the compound that embodiment 1-12 provides demonstrates relatively low toxicity to VERO cell, has druggability
Potentiality.Therefore, (first carry out the antitumor in-vitro screening of routine according to the general way of drug development, then carry out targetedly
Research), the compounds of this invention can be become salt by acid acceptable with human body or is mixed with new antitumor with pharmaceutical carrier
Medicine.
Claims (5)
1. ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound, it is characterised in that be specially with
The compound of lower structure:
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
。
The preparation of ring the most according to claim 1 third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound
Method, it is characterised in that concrete preparation process includes:
Formula (II) formula (III)
(1) the N-methyl ciprofloxacin shown in formula (III) is prepared with the N-methyl ciprofloxacin shown in formula (II) through hydrazinolysis reaction
Hydrazides, hydrazides (III) and potassium rhodanate are condensed to obtain ring the third fluoroquinolone C-3 amido thiourea (IV), and it is water-soluble at 5wt%NaOH
Liquid occur intramolecular cyclisation obtain ring the third fluoroquinolone C-3 triazole mercaptan (V),
；
Formula (IV) formula V
(2) be there is nucleophilic in ethanol with alpha-brominated 1-Phenylethanone. or alpha-brominated acetophenone derivs in the compound shown in formula V
Ring the third fluoroquinolone C-3 triazole sulfide ketone compounds shown in formula (VI) is made in substitution reaction,
Formula (VI), in formula (VI), R is、、、、 、、WithIn
At least one；
(3) by ring the third fluoroquinolone C-3 triazole sulfide ketone compounds shown in formula (VI) respectively with thiosemicarbazides in ice second
Acid occur condensation reaction obtain target compound ring the third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) chemical combination
Thing.
The preparation of ring the most according to claim 2 third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound
Method, it is characterised in that ring the third fluoroquinolone C-3 triazole sulfide ketone shown in formula (VI) and amino sulfur in described step (3)
The mol ratio of urea is 1 1.0 ~ 1.5.
Ring the most according to claim 1 third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound is in preparation
Application in antitumor drug.
Ring the most according to claim 4 third fluoroquinolone C-3 triazole sulfide ketone (thiosemicarbazone) compound is in preparation
Application in antitumor drug, it is characterised in that described antitumor drug is treatment bladder cancer, gastric cancer or pancreatic cancer drug.
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