CN104557973B - 3,3 '-methylene of a kind of chirality piperazine quinoline ring-bis-fluoro quinolone derivatives and its preparation method and application - Google Patents

3,3 '-methylene of a kind of chirality piperazine quinoline ring-bis-fluoro quinolone derivatives and its preparation method and application Download PDF

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CN104557973B
CN104557973B CN201410811507.5A CN201410811507A CN104557973B CN 104557973 B CN104557973 B CN 104557973B CN 201410811507 A CN201410811507 A CN 201410811507A CN 104557973 B CN104557973 B CN 104557973B
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methylene
piperazine
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CN104557973A (en
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闫强
胡海廷
吴书敏
倪礼礼
李涛
冯焱飞
高留州
谢玉锁
胡国强
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Henan University
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of chirality piperazine the 3 of quinoline ring, 3 ' di-2-ethylhexylphosphine oxide fluoro quinolone derivatives and its preparation method and application, use such as following formula I chemical structure of general formula:FormulaIn Formulas I, R is cyclopropyl or ethyl or fluoro ethyl；R1For hydrogen atom or methyl or ethyl；R2For hydrogen atom or methyl；X is nitrogen-atoms or hydrocarbon (CH) base or the substituted carbon atom of fluorine (F C) or the carbon atom (CH of methoxy substitution3O‑C).The chirality piperazine of the present invention the 3 of quinoline ring, 3 ' di-2-ethylhexylphosphine oxide fluoro quinolone derivatives, it is achieved that double fluoroquinolone skeletons withα,βThe superposition of beta-unsaturated ketone pharmacophore, 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

3,3 '-methylene of a kind of chirality piperazine quinoline ring-bis-fluoro quinolone derivatives and Its preparation method and application
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of chirality piperazine the 3 of quinoline ring, 3 '-methylene- Double fluoroquinolone derivative compounds, also relate to chirality piperazine the 3 of quinoline ring, 3 '-methylene-bis-fluoro quinolone derivatives Preparation method, and its application in antitumor drug.
Background technology
Tumor is one of maximum disease threatening human life's health.Owing to current antitumor drug toxicity is relatively big, suffer from The poor resistance of person, the cure rate causing tumor disease is low.Therefore, the antitumor drug of exploitation new structure is the most urgent.Though So find that the approach of new drug has multiple, but it is the most successful and most economical that the structural modification of existing medicine is still current new drug development Strategy.Effect target enzyme topoisomerase topoisomerase corresponding with in mammalian body based on antibacterial fluoroquinolone is in sequence Row and the similarity of function, can be converted into its anti-tumor activity by the structural modification of fluoroquinolone by its antibacterial activity.Meanwhile, Architectural feature based on fluoroquinolone carboxylic, can be converted in the important synthesizing activity such as fluoroquinolone aldehyde or hydrogenation fluoroquinolone Mesosome.The α being condensed in view of aldehyde and ketone, alpha, beta-unsaturated ketone architectural feature is also the important feature unit of natural chalcones, should Compounds has multiple pharmacologically active, is the important lead compound of new drug development.Further, since chiral drug selectivity High, toxic and side effects is low and receives much concern, the new drug in the exploitation of the current whole world has 70% to be above chipal compounds entity.
Summary of the invention
It is an object of the invention to provide a kind of chirality piperazine the 3 of quinoline ring, 3 '-methylene-bis-fluoro quinolone derivatives, There is antineoplastic action and effect, provide a kind of chirality piperazine the 3 of quinoline ring, 3 '-methylene-bis-fluoroquinolones to spread out simultaneously Biological preparation method.
In order to realize object above, the technical solution adopted in the present invention is: a kind of chirality piperazine the 3 of quinoline ring, 3 '- Methylene-bis-fluoro quinolone derivatives, its chemical structural formula is as shown in logical formula (I):
In Formulas I, R is ethyl or cyclopropyl or 2-fluoro ethyl；
R in Formulas I1For hydrogen atom or methyl or ethyl；
R in Formulas I2For hydrogen atom or methyl；
In Formulas I, X is CH or N or the substituted carbon atom of fluorine (F-C) or the carbon atom (CH of methoxy substitution3O-C)。
This compound is left-handed photosensitiveness (), and the absolute configuration of chiral carbon (* C) is S type, the chemical combination of following structure Thing:
A kind of chirality piperazine of the present invention the 3 of quinoline ring, the preparation method of 3 '-methylene-bis-fluoro quinolone derivatives, It is prepared from the fluoroquinolone aldehydic acid shown in formula (II) for raw material,
Concrete preparation process is as follows:
1) by fluoroquinolone carboxylic (norfloxacin (II-1), pefloxacin (II-2), ring the third sand respectively shown in formula (II) Star (II-3), N-methyl ciprofloxacin (II-4), enrofloxacin (II-5), enoxacin (II-6), fleroxacin (II-7), Lip river U.S. husky star (II-8), Gatifloxacin (II-9)) prepare the 2,3-dihydro fluorine quinoline promise shown in formula (III) through sodium borohydride reduction decarboxylation Ketone (corresponding compound is respectively III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9)；
2) by levofloxacin with reference to step 1) described method is through sodium borohydride reduction decarboxylation, then reduction decarboxylate is depended on Secondary through formylated, oxidation make the fluoroquinolone C-6 formaldehyde shown in formula (IV), step 1) and step 2) Detailed operating procedures can With reference literature (Kondo H, Sakamoto F, et al.Studies on prodrugs.7.Synthesis and antimicrobial activity of 3-formyl-quinolonederivatives,J.Med.Chem.1988,31 (1): the research of 221-225. prodrug. the synthesis of quinolinones-3-aldehyde and antimicrobial acivity) described in method；
Concrete preparation process is as follows:
3) by compound dissolution shown in compound shown in formula (III) and formula (IV) in dehydrated alcohol, in piperidines or three second Back flow reaction 12～24 hours under the catalysis of amine, place room temperature, filters, and collects the solid produced, by suitable solvent recrystallization, Prepare target compound shown in formula (I) (corresponding compound is respectively I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9),
In formula (I), formula (II), formula (III), R is ethyl or cyclopropyl or 2-fluoro ethyl；
R in formula (I), formula (II), formula (III)1For hydrogen atom or methyl or ethyl；
R in formula (I), formula (II), formula (III)2For hydrogen atom or methyl；
In formula (I), formula (II), formula (III), X is nitrogen-atoms (N) or hydrocarbon (CH) or the substituted carbon atom of fluorine (F-C) or first Epoxide substituted carbon atom (CH3O-C)。
As further improving, the dihydro fluoroquinolone shown in formula III and the fluoroquinolone aldehyde shown in Formula IV mole For 1:1.0～1.2.
Described alkali is pyridine, triethylamine, piperidines, morpholine, piperazine, potassium hydroxide, sodium hydroxide, calcium hydroxide, carbonic acid At least one in potassium and sodium carbonate.
Described chirality piperazine 3,3 '-methylene of quinoline ring-bis-fluoro quinolone derivatives are preparing antitumor drug In application.
Described antitumor drug is treatment bladder cancer, gastric cancer or pancreatic cancer drug.
Chirality piperazine of the present invention the 3 of quinoline ring, 3 '-methylene-bis-fluoroquinolones principle of hybridization based on pharmacophore, will Fluoroquinolone pharmacophore and α, alpha, beta-unsaturated ketone pharmacophore is effectively combined, and design has synthesized chirality " testing afloqualone chalcone " and spread out Biological, it is achieved that the complementation of structure and the superposition of pharmacophore activity, reach the effect of potentiation toxicity reduction, can be as brand new Antitumor drug is developed.
Detailed description of the invention
Below by specific embodiment, technical scheme is described in detail.
Embodiment 1
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-ethyl-6-fluoro-7-piperazine- 1-base-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-1), its chemical structural formula is:
I.e. R in Formulas I is ethyl, R1And R2For hydrogen atom, X is hydrocarbon group.
The preparation method of this compound is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-quinoline Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and 1-ethyl-6-fluoro-7-piperazine-1-base-2,3-dihydro-quinoline-4 (1H)-one (III-1) 0.44g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, back flow reaction 24h.Place 12h, The solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtains pale yellow crystals thing (I-1), productivity 82%, M.p.228～232 DEG C.1H NMR(400MHz,DMSO-d6) δ: 7.91～7.88 (brs, 2H, 2-H, 3-CH=), 7.76 (d, 1H, 5-H), 7.37 (d, 1H, 5 '-H), 6.96 (d, 1H, 8 '-H), 4.55～4.24 (m, 5H, OCH2CHN and NCH 2CH3),3.55 (s, 2H, 2 '-H), 3.32～2.46 (m, 16H, piperazine-H), 2.23 (s, 3H ,-NCH3), 1.34～1.30 (m, 6H, NCH2 CH 3 And 3-CH3)；MS(m/z):605[M+H]+, calculate (C33H38F2N6O3):604.71。
Embodiment 2
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-ethyl-6-fluoro-7-(4-first Base piperazine-1-base)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl] and-quinoline-4 (1H)-one (I-2), its chemical structural formula For:
I.e. R in Formulas I is ethyl, R1For methyl, R2For hydrogen atom, X is CH.
The preparation method of this compound is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-quinoline Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and the fluoro-7-of 1-ethyl-6-(4-methylpiperazine-1-yl)-2,3-dihydro-quinoline- 4 (1H)-one (III-2) 0.50g (1.7mmol) is dissolved in 20mL dehydrated alcohol, drips triethylamine 0.2mL, back flow reaction 20h.Place 12h, the solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtain pale yellow crystals thing (I-2), produce Rate 85%, m.p.225～227 DEG C.1H NMR(400MHz,DMSO-d6) δ: 7.90～7.87 (brs, 2H, 2-H, 3-CH=), 7.78 (d, 1H, 5-H), 7.36 (d, 1H, 5 '-H), 6.97 (d, 1H, 8 '-H), 4.55～4.26 (m, 5H, OCH2CHN and NCH 2CH3), 3.55 (s, 2H, 2 '-H), 3.34～2.47 (m, 16H, piperazine-H), 2.23,2.24 (2s, 6H, 2 × NCH3), 1.33～1.28 (m, 6H, NCH2 CH 3And 3-CH3)；MS(m/z):619[M+H]+, calculate (C34H40F2N6O3):618.73。
Embodiment 3
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-cyclopropyl-6-fluoro-7-piperazine Piperazine-1-base-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-3), its chemical structural formula is:
I.e. R in Formulas I is cyclopropyl, R1And R2For hydrogen atom, X is hydrocarbon group.
The preparation method of this compound is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-quinoline Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and 1-cyclopropyl-6-fluoro-7-piperazine-1-base-2,3-dihydro-quinoline-4 (1H)- Ketone (III-3) 0.52g (1.8mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, back flow reaction 22h.Place 24h, the solid that filter collection produces, with DMF-ethanol (V:V=5:1) recrystallization, obtain pale yellow crystals thing (I-3), productivity 86%, M.p.232～234 DEG C.1H NMR(400MHz,DMSO-d6) δ: 7.92～7.88 (brs, 2H, 2-H, 3-CH=), 7.78 (d, 1H, 5-H), 7.35 (d, 1H, 5 '-H), 6.97 (d, 1H, 8 '-H), 4.57～4.26 (m, 3H, OCH2CHN), 3.56～3.46 (m, 3H, 2 '-H and 1 "-H), 3.37～2.53 (m, 16H, piperazine-H), 2.22 (s, 3H, NCH3), 1.34～1.03 (m, 7H, CH3, 2 "-H and 3 "-H)；MS(m/z):617[M+H]+, value of calculation (C34H38F2N6O3):616.72。
Embodiment 4
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-cyclopropyl-6-fluoro-7-(4- Thyl-piperazin-1-base)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl] and-quinoline-4 (1H)-one (I-4), its chemistry knot Structure formula is:
I.e. R in Formulas I is cyclopropyl, R1For methyl, R2For hydrogen atom, X is hydrocarbon group.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and the fluoro-7-of 1-cyclopropyl-6-(4-methylpiperazine-1-yl)-2,3-dihydro- Quinoline-4 (1H)-one (III-4) 0.49g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, back flow reaction 24h.Place 12h, the solid that filter collection produces, with DMF-ethanol (V:V=5:1) recrystallization, obtain pale yellow crystals thing (I-4), produce Rate 86%, m.p.232～234 DEG C.1H NMR(400MHz,DMSO-d6) δ: 7.91～7.88 (brs, 2H, 2-H, 3-CH=), 7.78 (d, 1H, 5-H), 7.36 (d, 1H, 5 '-H), 7.03 (d, 1H, 8 '-H), 4.57～4.28 (m, 3H, OCH2CHN),3.56 ～3.45 (m, 3H, 2 '-H and 1 "-H), 3.36～2.51 (m, 16H, piperazine-H), 2.23,2.25 (2s, 6H, 2 × NCH3), 1.35～1.07 (m, 7H, CH3, 2 "-H and 3 "-H)；MS(m/z):631[M+H]+, value of calculation (C35H40F2N6O3):630.74。
Embodiment 5
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-cyclopropyl-6-fluoro-7-(4- Ethyl-piperazin-1-base)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl] and-quinoline-4 (1H)-one (I-5), its chemistry knot Structure formula is:
I.e. R in Formulas I is cyclopropyl, R1For ethyl, R2For hydrogen atom, X is hydrocarbon group.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and the fluoro-7-of 1-cyclopropyl-6-(4-ethyl piperazidine-1-base)-2,3-dihydro- Quinoline-4 (1H)-one (III-6) 0.58g (1.9mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, back flow reaction 23h.Place 24h, the solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtain pale yellow crystals thing (I-5), produce Rate 87%, m.p.228～230 DEG C.1H NMR(400MHz,DMSO-d6) δ: 8.07 (s, 1H, 2-H), 7.87 (s, 1H, 3-CH =), 7.78 (d, 1H, 5-H), 7.38 (d, 1H, 5 '-H), 6.96 (d, 1H, 8 '-H), 4.56～4.32 (m, 3H, OCH2CHN), 3.57～3.46 (m, 3H, 2 '-H and 1 "-H), 3.37～2.53 (m, 16H, piperazine-H), 2.21～2.25 (m, 5H, 1 " ' and NCH3), 1.32～0.97 (m, 10H, 2 × CH3, 2 "-H and 3 "-H)；MS(m/z):645[M+H]+, calculate (C36H42F2N6O3): 644.77。
Embodiment 6
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-cyclopropyl-6-fluoro-7-piperazine Piperazine-1-base-2,3-dihydro-[1,8] naphthyridines-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-6), its chemical structural formula For:
I.e. R ethyl in Formulas I, R1And R2For hydrogen atom, X is nitrogen-atoms.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and 1-ethyl-6-fluoro-7-base piperazine-1-base-2,3-dihydro-[1,8] naphthalene Pyridine-4 (1H)-one (III-6) 0.44g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drips triethylamine 0.4mL, back flow reaction 24h.Place 24h, the solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtain pale yellow crystals thing (I-6), produce Rate 77%, m.p.226～228 DEG C.1H NMR(400MHz,DMSO-d6)δ:8.05(s,1H,2-H),7.87(s,1H,3-CH =), 7.80,7.72 (2d, 5-H and 5 '-H), 4.58～4.30 (m, 5H, OCH2CHN and NCH 2CH3),3.67(s,2H,2′-H), 3.37～2.53 (m, 16H, piperazine-H), 1.37～1.07 (m, 6H, NCH2 CH 3And CH3)；MS(m/z):606[M+H]+, calculate Value (C32H37F2N7O3):605.69。
Embodiment 7
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-(2-fluoro ethyl)-6,8-bis- Fluoro-7-(4-methylpiperazine-1-yl)-2,3-dihydro-quinoline-4 (1H)-3-pitch methyl]-quinoline-4 (1H)-one (I-7), it is changed Structural formula is:
I.e. R in Formulas I is 2-fluoro ethyl, R1For methyl, R2For hydrogen atom, X is CF.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and 1-(2-fluoro ethyl)-6, the fluoro-7-of 8-bis-(4-methylpiperazine-1-yl)-2, 3-dihydro-quinoline-4 (1H)-one (III-7) 0.52g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, Back flow reaction 18h.Place 20h, the solid that filter collection produces, with DMF-ethanol (V:V=5:1) recrystallization, obtain pale yellow crystals Thing (I-7), productivity 81%, m.p.233～235 DEG C.1H NMR(400MHz,DMSO-d6) δ: 8.06 (s, 1H, 2-H), 7.88～ 7.75 (m, 3H, 3-CH=, 5-H and 5 '-H), 4.86 (t, 2H, FCH2),4.67(t,2H,FCH2 CH 2N), 4.56～4.34 (m, 3H,OCH2CHN), 3.58 (s, 2H, 2 '-H), 3.36～2.57 (m, 16H, piperazine-H), 2.24,2.28 (2s, 6H, 2 × NCH3), 1.35(d,3H,CH3)；MS(m/z):655[M+H]+, value of calculation (C34H38F4N6O3):654.71。
Embodiment 8
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-ethyl-6, the fluoro-7-of 8-bis- (3-methylpiperazine-1-yl)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-8), its chemistry Structural formula is:
I.e. R in Formulas I is ethyl, R1For hydrogen atom, R2For methyl, X is CF.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and 1-ethyl-6, the fluoro-7-of 8-bis-(3-methylpiperazine-1-yl)-2,3-bis- Hydrogen-quinoline-4 (1H)-one (III-8) 0.49g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drips piperidines 0.2mL, backflow Reaction 20h.Place 24h, the solid that filter collection produces, with DMF-ethanol (V:V=5:1) recrystallization, obtain pale yellow crystals thing (I- 8), productivity 76%, m.p.226～228 DEG C.1H NMR(400MHz,DMSO-d6) δ: 8.03 (s, 1H, 2-H), 7.88～7.70 (m, 3H, 3-CH=, 5-H and 5 '-H), 4.57～4.36 (m, 3H, OCH2CHN),4.28(q,2H,NCH 2CH3),3.58(s,2H, 2 '-H), 3.36～2.55 (m, 16H, piperazine-H), 2.24 (s, 3H, NCH3), 1.35～1.27 (m, 6H, 2 × CH3)；MS(m/ z):637[M+H]+, value of calculation (C34H39F3N6O3):636.72。
Embodiment 9
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[1-cyclopropyl-6-fluoro-7-(3- Methylpiperazine-1-yl)-8-methoxyl group-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-9), Its chemical structural formula is:
I.e. R in Formulas I is cyclopropyl, R1For hydrogen atom, R2For methyl, X methoxyl group-carbon-based group.
The preparation method of above-claimed cpd is: take the fluoro-7-of 6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)- Quinoline-4 (1H)-one (VI) 0.55g (1.6mmol) and the fluoro-7-of 1-cyclopropyl-6-(3-methylpiperazine-1-yl)-8-methoxyl group- 2,3-dihydro-quinoline-4 (1H)-one (III-9) 0.58g (1.8mmol) are dissolved in 20mL dehydrated alcohol, drip piperidines 0.2mL, back flow reaction 12h.Place 24h, the solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtain faint yellow Crystal (I-9), productivity 78%, m.p.231～232 DEG C.1H NMR(400MHz,DMSO-d6)δ:8.07(s,1H,5-H), 7.93～7.74 (m, 3H, 3-CH=, 5-H and 5 '-H), 4.56～4.35 (m, 3H, OCH2CHN),3.88(s,3H,OCH3), 3.67～3.46 (m, 3H, 2 '-H and 1 "-H), 3.37～2.56 (m, 16H, piperazine-H), 1.35～0.99 (m, 10H, 2 × CH3, 2 "-H and 3 ' '-H)；MS(m/z):661[M+H]+, value of calculation (C36H42F2N6O4):660.77。
Compound III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 in above-mentioned 9 embodiments, The synthesis of III-9 and the synthesis Detailed operating procedures of compound VI are referred to document (Kondo H, Sakamoto F, et al.Studies on prodrugs.7.Synthesis and antimicrobial activity of 3-formyl- Quinolone derivatives, J.Med.Chem.1988,31 (1): the research of 221-225. prodrug. quinolinones-3-aldehyde Synthesis and antimicrobial acivity) described in method.
Test example
One, embodiment 1-9 provides chirality piperazine the body of 3,3 '-methylene-bis-fluoroquinolone compounds of quinoline ring Outer antitumor cytolytic activity
1, test sample
9 the new chirality piperazines provided with embodiment 1-9 3,3 '-methylene-bis-fluoroquinolone chemical combination of quinoline ring Thing compound and classical antitumor TOPO inhibitor 10-hydroxycamptothecine (HC) and parent compound levofloxacin (LOF) are for supplying Test agent, totally 11 kinds, wherein HC and LOF is matched group, and embodiment 1-9 sample is experimental group, with without any compound DMSO is blank 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 11 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) respectively, be configured to 1.0 × 10-2μ mol·L-1The storing solution of concentration, afterwards with the RPMI-1640 culture fluid of the calf serum that mass percent concentration is 10% by 10 Storing solution is diluted to have 6 Concentraton gradient (1.0,10.0,20.0,30.0,40.0,50.0 μm ol L by times dilution method-1) Working solution；
Take the logarithm the urinary bladder carcinoma T24 cell line of trophophase, gastric cancer HGC823 cell, gastric cancer HGC27 cell, cancer of pancreas Panc-1 Cell and cancer of pancreas Capan-1 cell and VERO cell strain, be inoculated in 96 orifice plates with 7000, every hole cell, and be provided with without medicine pair According to hole, being separately added into the working solution with 6 Concentraton gradient of above-mentioned 11 kinds of samples subsequently, after 48 hours, every hole adds 5g L– 1MTT (tetrazolium bromide) aqueous solution 10 μ L, adding 100 μ L mass percent concentrations after continuing to cultivate 4 hours is the dodecyl of 10% Sodium sulfate (SDS) aqueous solution is cultivated 24 hours, then measures OD value at 570nm wavelength by microplate reader；
(3) test sample of the variable concentrations suppression ratio to cancerous cell is calculated by following shown formula,
Inhibition of cancer cell rate=[(1-experimental group OD value)/blank group 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 1-9 provides The activity of the activity of parent compound levofloxacin, especially majority of compounds is better than the activity of comparison hydroxycamptothecin.More Meaningfully, the compound that embodiment 1-9 provides demonstrates relatively low toxicity to VERO cell, has the potentiality of druggability. Therefore, it is the antitumor in-vitro screening first carrying out routine according to the general way of drug development, studies the most targetedly, So the compound of the present invention has strong anti-tumor activity and relatively low toxicity, can by acceptable with human body acid become salt or It is mixed with antitumor drug with pharmaceutical carrier.

Claims (6)

1. a chirality piperazine the 3 of quinoline ring, 3 '-methylene-bis-fluoro quinolone derivatives, it is characterised in that this compound For left-handed photosensitiveness, the absolute configuration of chiral carbon is S type, the compound of following structure:
Or
Or
Or
Or
Or
Or
Or
Or
。
The preparation of 3,3 '-methylene of chirality piperazine the most according to claim 1 quinoline ring-bis-fluoro quinolone derivatives Method, it is characterised in that concrete preparation process includes:
(1) with the fluoroquinolone carboxylic shown in formula (II) as raw material, shown in formula (III) 2 are prepared through sodium borohydride reduction decarboxylation, 3-dihydro fluoroquinolone,
Formula (II)
Formula (III)
Wherein, R is ethyl or cyclopropyl or 2-fluoro ethyl,
R1For hydrogen atom or methyl or ethyl,
R2For hydrogen atom or methyl,
X is N, CH, the substituted carbon atom of fluorine or the carbon atom of methoxy substitution；
(2) by levofloxacin through sodium borohydride reduction decarboxylation, then reduction decarboxylate is made formula through formylated, oxidation successively (IV) the fluoroquinolone C-6 formaldehyde shown in；
Formula (IV)
(3) by the compound shown in the compound shown in formula (III) and formula (IV) in dehydrated alcohol, in alkalescence condition next time Flow 12 ~ 24 hours, condensation reaction occurs, after reaction terminates, the post-treated chirality piperazine obtained shown in formula (I) quinoline ring 3,3 ' methylene-bis-fluoro quinolone derivatives.
The preparation of 3,3 '-methylene of chirality piperazine the most according to claim 2 quinoline ring-bis-fluoro quinolone derivatives The mol ratio of method, it is characterised in that 2 shown in described formula (III), 3-dihydro fluoroquinolone and the compound shown in formula (IV) For 1:1.0 ~ 1.2.
The preparation of 3,3 '-methylene of chirality piperazine the most according to claim 2 quinoline ring-bis-fluoro quinolone derivatives Method, it is characterised in that described alkali is pyridine, triethylamine, piperidines, morpholine, piperazine, potassium hydroxide, sodium hydroxide, hydroxide At least one in calcium, potassium carbonate and sodium carbonate.
5. 3,3 '-methylene-bis-fluoro quinolone derivatives of chirality piperazine described in claim 1 quinoline ring are anti-swollen in preparation Application in tumor medicine.
3,3 '-methylene of chirality piperazine the most according to claim 5 quinoline ring-bis-fluoro quinolone derivatives are 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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