CN104557973A - 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative - Google Patents
3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative Download PDFInfo
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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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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses a 3,3'-methene-difluoroquinolone derivative of a chiral oxazine quinoline ring as well as a preparation method and application of the 3,3'-methene-difluoroquinolone derivative. The 3,3'-methene-difluoroquinolone derivative has a chemical general structural formula I shown in the specification, wherein R represents cyclopropyl or ethyl or fluoroethyl; R1 represents a hydrogen atom or methyl or ethyl; R2 represents a hydrogen atom or methyl; X represents a nitrogen atom or a hydrocarbon (CH) group or a fluoro-substituted carbon atom (F-C) or a methoxyl-substituted carbon atom (CH3O-C). The 3,3'-methene-difluoroquinolone derivative of the chiral oxazine quinoline ring, disclosed by the invention, can be used for realizing the superposition of a difluoroquinolone framework and alpha, beta-unsaturated ketone pharmacophores, so that the antitumor activity of a new compound is improved, the toxic and side effects on normal cells can be reduced, and the 3,3'-methene-difluoroquinolone derivative can be used as an antitumor active substance for developing an antitumor drug of a totally new structure.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to 3 of a kind of Shou oxazine quinoline ring, 3 '-methylene radical-bis-fluoroquinolone derivative compound, also relate to Shou oxazine and 3 of quinoline ring simultaneously, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative, and its application in antitumor drug.
Background technology
Tumour is one of maximum disease threatening human life's health.Because current antitumor drug toxicity is comparatively large, the tolerance of patient is poor, causes the curative ratio of tumor disease low.Therefore, the antitumor drug of development of new structure is day by day urgent.Although find that the approach of new drug has multiple, the successful and the most most economical strategy of current new drug development is still to the structural modification of existing medicine.Based on the similarity of the effect target enzyme-topoisomerase of the antibacterial fluoroquinolone topoisomerase corresponding in mammalian body in sequence and function, its anti-microbial activity is converted into its anti-tumor activity by the structural modification by fluoroquinolone.Meanwhile, based on the constitutional features of fluoroquinolone carboxylic, the composite reactive intermediate that fluoroquinolone aldehyde or hydrogenation fluoroquinolone etc. are important can be converted into.Consider that the alpha, beta-unsaturated ketone constitutional features of aldehyde and ketone condensation is also the important feature unit of natural chalcones, this compounds has multiple pharmacologically active, is the important lead compound of new drug development.In addition, because chiral drug selectivity is high, toxic side effect is low and receive much concern, the new drug in the exploitation of the current whole world has more than 70% to be chipal compounds entity.
Summary of the invention
The object of this invention is to provide 3 of a kind of Shou oxazine quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative, there is antineoplastic action and effect, provide 3 of a kind of Shou oxazine quinoline ring simultaneously, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative.
In order to realize above object, the technical solution adopted in the present invention is: a kind of Shou oxazine 3 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative, and its chemical structural formula is as shown in general formula (I):
In formula I, R is ethyl or cyclopropyl or 2-fluoro ethyl;
R in formula I
1for hydrogen atom or methyl or ethyl;
R in formula I
2for hydrogen atom or methyl;
In formula I, X is the carbon atom (F-C) of CH or N or fluorine replacement or the carbon atom (CH of methoxy substitution
3o-C).
This compound is left-handed photosensitiveness (-), and the absolute configuration of chiral carbon (* C) is S type, is specially the compound of following structure:
A kind of Shou oxazine of the present invention 3 of quinoline ring, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative is that raw material is prepared from the fluoroquinolone aldehydic carboxylic acid shown in formula (II),
Concrete preparation process is as follows:
1) by the fluoroquinolone carboxylic (norfloxicin (II-1) respectively shown in formula (II), Pefloxacin (II-2), Ciprofloxacin (II-3), N-methyl Ciprofloxacin (II-4), Enrofloxacin (II-5), enoxacin (II-6), fleroxacin (II-7), lomefloxacin (II-8), Gatifloxacin (II-9)) obtain 2 shown in formula (III) through sodium borohydride reduction decarboxylation, (corresponding compound is respectively III-1 to 3-dihydro fluoroquinolone, 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, decarboxylate will be reduced again successively through formylation, the fluoroquinolone C-6 formaldehyde shown in formula (IV) is made in oxidation, step 1) and step 2) Detailed operating procedures can reference literature (Kondo H, Sakamoto F, et al.Studies on prodrugs.7.Synthesis and antimicrobialactivity of 3-formyl-quinolonederivatives, J.Med.Chem.1988, the research of 31 (1): 221-225. prodrugs. the synthesis of quinolone-3-aldehyde and antimicrobial acivity) described in method,
Concrete preparation process is as follows:
3) by compound dissolution shown in compound formula (III) Suo Shi and formula (IV) in dehydrated alcohol, under the catalysis of piperidines or triethylamine, back flow reaction 12 ~ 24 hours, places room temperature, filter, collect the solid produced, by suitable solvent recrystallization, (corresponding compound is respectively I-1, I-2, I-3 to obtained target compound shown in formula (I), I-4, I-5, I-6, I-7, I-8, I-9)
R is ethyl or cyclopropyl or 2-fluoro ethyl in formula (I), formula (II), formula (III);
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 the carbon atom (F-C) of nitrogen-atoms (N) or hydrocarbon (CH) or fluorine replacement or the carbon atom (CH of methoxy substitution
3o-C).
As further improvement, the dihydro fluoroquinolone shown in formula III and the fluoroquinolone aldehyde shown in formula VI mole be 1:1.0 ~ 1.2.
Described alkali is at least one in pyridine, triethylamine, piperidines, morpholine, piperazine, potassium hydroxide, sodium hydroxide, calcium hydroxide, salt of wormwood and sodium carbonate.
Described Shou oxazine 3 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative is preparing the application in antitumor drug.
Described antitumor drug is treatment bladder cancer, cancer of the stomach or pancreatic cancer drug.
Shou oxazine of the present invention 3 of quinoline ring, 3 '-methylene radical-bis-fluoroquinolone is based on the principle of hybridization of pharmacophore, by fluoroquinolone pharmacophore and α, alpha, beta-unsaturated ketone pharmacophore effectively combines, design and synthesis chirality " testing afloqualone cinnamophenone " derivative, achieve the complementation of structure and the superposition of pharmacophore activity, reach the effect of synergy toxicity reduction, can be used as the antitumor drug exploitation of brand new.
Embodiment
Below by specific embodiment, technical scheme of the present invention 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-[the fluoro-7-piperazine of 1-ethyl-6--1-base-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-1), its chemical structural formula is:
Namely the R in formula I is ethyl, R
1and R
2for hydrogen atom, X is hydrocarbon group.
The preparation method of this compound is: get 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-piperazine of 1-ethyl-6--1-base-2,3-dihydro-quinoline-4 (1H)-one (III-1) 0.44g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drip piperidines 0.2mL, back flow reaction 24h.Place 12h, the solid that filter collection produces, with DMF-ethanol (V:V=3:1) recrystallization, obtain pale yellow crystals thing (I-1), productive rate 82%, m.p.228 ~ 232 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN and N
cH 2cH
3), 3.55 (s, 2H, 2 '-H), 3.32 ~ 2.46 (m, 16H, piperazine-H), 2.23 (s, 3H ,-NCH
3), 1.34 ~ 1.30 (m, 6H, NCH
2 cH 3and 3-CH
3); MS (m/z): 605 [M+H]
+, calculate (C
33h
38f
2n
6o
3): 604.71.
Embodiment 2
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-of 1-ethyl-6-(4-methylpiperazine-1-yl)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-2), its chemical structural formula is:
Namely the R in formula I is ethyl, R
1for methyl, R
2for hydrogen atom, X is CH.
The preparation method of this compound is: get 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-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, drip 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), productive rate 85%, m.p.225 ~ 227 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN and N
cH 2cH
3), 3.55 (s, 2H, 2 '-H), 3.34 ~ 2.47 (m, 16H, piperazine-H), 2.23,2.24 (2s, 6H, 2 × NCH
3), 1.33 ~ 1.28 (m, 6H, NCH
2 cH 3and 3-CH
3); MS (m/z): 619 [M+H]
+, calculate (C
34h
40f
2n
6o
3): 618.73.
Embodiment 3
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-piperazine of 1-cyclopropyl-6--1-base-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-3), its chemical structural formula is:
Namely the R in formula I is cyclopropyl, R
1and R
2for hydrogen atom, X is hydrocarbon group.
The preparation method of this compound is: get 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-piperazine of 1-cyclopropyl-6--1-base-2,3-dihydro-quinoline-4 (1H)-one (III-3) 0.52g (1.8mmol) is dissolved in 20mL dehydrated alcohol, drip 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), productive rate 86%, m.p.232 ~ 234 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN), 3.56 ~ 3.46 (m, 3H, 2 '-H and 1 "-H), 3.37 ~ 2.53 (m, 16H, piperazine-H), 2.22 (s, 3H, NCH
3), 1.34 ~ 1.03 (m, 7H, CH
3, 2 "-H and 3 "-H); MS (m/z): 617 [M+H]
+, calculated value (C
34h
38f
2n
6o
3): 616.72.
Embodiment 4
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-of 1-cyclopropyl-6-(4-thyl-piperazin-1-base)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-4), its chemical structural formula is:
Namely the R in formula I is cyclopropyl, R
1for methyl, R
2for hydrogen atom, X is hydrocarbon group.
The preparation method of above-claimed cpd is: get 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, drip 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), productive rate 86%, m.p.232 ~ 234 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN), 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 × NCH
3), 1.35 ~ 1.07 (m, 7H, CH
3, 2 "-H and 3 "-H); MS (m/z): 631 [M+H]
+, calculated value (C
35h
40f
2n
6o
3): 630.74.
Embodiment 5
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-of 1-cyclopropyl-6-(4-ethyl-piperazin-1-base)-2,3-dihydro-quinoline-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-5), its chemical structural formula is:
Namely the R in formula I is cyclopropyl, R
1for ethyl, R
2for hydrogen atom, X is hydrocarbon group.
The preparation method of above-claimed cpd is: get 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, drip 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), productive rate 87%, m.p.228 ~ 230 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN), 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 NCH
3), 1.32 ~ 0.97 (m, 10H, 2 × CH
3, 2 "-H and 3 "-H); MS (m/z): 645 [M+H]
+, calculate (C
36h
42f
2n
6o
3): 644.77.
Embodiment 6
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-piperazine of 1-cyclopropyl-6--1-base-2,3-dihydro-[1,8] naphthyridines-4 (1H)-one-3-pitches methyl]-quinoline-4 (1H)-one (I-6), its chemical structural formula is:
Namely the R ethyl in formula I, R
1and R
2for hydrogen atom, X is nitrogen-atoms.
The preparation method of above-claimed cpd is: get 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] naphthyridines-4 (1H)-one (III-6) 0.44g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drip 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), productive rate 77%, m.p.226 ~ 228 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN and N
cH 2cH
3), 3.67 (s, 2H, 2 '-H), 3.37 ~ 2.53 (m, 16H, piperazine-H), 1.37 ~ 1.07 (m, 6H, NCH
2 cH 3and CH
3); MS (m/z): 606 [M+H]
+, calculated value (C
32h
37f
2n
7o
3): 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, the fluoro-7-of 8-bis-(4-methylpiperazine-1-yl)-2,3-dihydro-quinoline-4 (1H)-3-pitches methyl]-quinoline-4 (1H)-one (I-7), its chemical structural formula is:
Namely the R in formula I is 2-fluoro ethyl, R
1for methyl, R
2for hydrogen atom, X is CF.
The preparation method of above-claimed cpd is: get 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, drip 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), productive rate 81%, m.p.233 ~ 235 DEG C.
1h NMR (400MHz, DMSO-d
6) δ: 8.06 (s, 1H, 2-H), 7.88 ~ 7.75 (m, 3H, 3-CH=, 5-H and 5 '-H), 4.86 (t, 2H, FCH
2), 4.67 (t, 2H, FCH
2 cH 2n), 4.56 ~ 4.34 (m, 3H, OCH
2cHN), 3.58 (s, 2H, 2 '-H), 3.36 ~ 2.57 (m, 16H, piperazine-H), 2.24,2.28 (2s, 6H, 2 × NCH
3), 1.35 (d, 3H, CH
3); MS (m/z): 655 [M+H]
+, calculated value (C
34h
38f
4n
6o
3): 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 chemical structural formula is:
Namely the R in formula I is ethyl, R
1for hydrogen atom, R
2for methyl, X is CF.
The preparation method of above-claimed cpd is: get 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-dihydro-quinoline-4 (1H)-one (III-8) 0.49g (1.6mmol) is dissolved in 20mL dehydrated alcohol, drip piperidines 0.2mL, back flow 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), productive rate 76%, m.p.226 ~ 228 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN), 4.28 (q, 2H, N
cH 2cH
3), 3.58 (s, 2H, 2 '-H), 3.36 ~ 2.55 (m, 16H, piperazine-H), 2.24 (s, 3H, NCH
3), 1.35 ~ 1.27 (m, 6H, 2 × CH
3); MS (m/z): 637 [M+H]
+, calculated value (C
34h
39f
3n
6o
3): 636.72.
Embodiment 9
(S) the fluoro-7-of-6-(4-thyl-piperazin-1-base)-1,8-(3,1-oxygen propyl group)-3-[the fluoro-7-of 1-cyclopropyl-6-(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:
Namely the R in formula I is cyclopropyl, R
1for hydrogen atom, R
2for methyl, X methoxyl group-carbon-based group.
The preparation method of above-claimed cpd is: get 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) is 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 pale yellow crystals thing (I-9), productive rate 78%, m.p.231 ~ 232 DEG C.
1h NMR (400MHz, DMSO-d
6) 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, OCH
2cHN), 3.88 (s, 3H, OCH
3), 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 × CH
3, 2 " and-H and 3 ' '-H); MS (m/z): 661 [M+H]
+, calculated value (C
36h
42f
2n
6o
4): 660.77.
Compound III-1 in above-mentioned 9 embodiments, III-2, III-3, III-4, III-5, III-6, III-7, III-8, the synthesis of III-9 and the synthesis Detailed operating procedures of compound VI can reference literature (Kondo H, Sakamoto F, et al.Studieson prodrugs.7.Synthesis and antimicrobial activity of 3-formyl-quinolone derivatives, J.Med.Chem.1988, the research of 31 (1): 221-225. prodrugs. the synthesis of quinolone-3-aldehyde and antimicrobial acivity) described in method.
Test example
One, the Shou oxazine that provides of embodiment 1-9 3 of quinoline ring, the anti tumor activity in vitro of 3 '-methylene radical-bis-fluoroquinolone compound measures
1, test sample
9 that provide with embodiment 1-9 new Shou oxazines 3 of quinoline ring, 3 '-methylene radical-bis-fluoroquinolone compound compound and classical antitumor TOPO inhibitor 10-hydroxycamptothecine (HC) and parent compound levofloxacin (LOF) are test sample, totally 11 kinds, wherein HC and LOF is control group, embodiment 1-9 sample is experimental group, not add the DMSO of any compound for blank group.
Experiment JEG-3 is respectively T24 transitional cell bladder carcinoma cell line, HGC823 stomach cancer cell, HGC27 stomach cancer cell, Panc-1 pancreatic cancer cell, Capan-1 pancreatic cancer cell, and JEG-3 is all bought from Chinese Academy of Sciences's Shanghai cell bank.Normal cell adopts VERO African green monkey kidney cell, buys and leads to growth Science and Technology Ltd. in Shanghai.
2, measuring method
The concrete steps of measuring method are:
(1) first use dimethyl sulfoxide (DMSO) (DMSO) to dissolve respectively above-mentioned 11 kinds of test samples, be mixed with 1.0 × 10
-2μm olL
-1the storing solution of concentration is that storing solution to be diluted to by 10 times of dilution methods and to have 6 concentration gradients (1.0,10.0,20.0,30.0,40.0,50.0 μm of olL by the RPMI-1640 nutrient solution of the calf serum of 10% afterwards with mass percent concentration
-1) working fluid;
The urinary bladder carcinoma T24 cell line of taking the logarithm vegetative period, cancer of the stomach HGC823 cell, cancer of the stomach HGC27 cell, carcinoma of the pancreas Panc-1 cell and carcinoma of the pancreas Capan-1 cell and VERO cell strain, 96 orifice plates are inoculated in 7000, every hole cell, and be provided with without medicine control wells, add the working fluid with 6 concentration gradients of above-mentioned 11 kinds of samples subsequently respectively, after 48 hours, every hole adds 5gL
– 1mTT (tetrazolium bromide) aqueous solution 10 μ L, continue cultivation add after 4 hours 100 μ L mass percent concentrations be 10% sodium lauryl sulphate (SDS) aqueous solution cultivate 24 hours, then measure OD value by microplate reader at 570nm wavelength place;
(3) by the test sample of formulae discovery different concns shown in following to the inhibiting rate of cancer cells,
Inhibition of cancer cell rate=[(1-experimental group OD value)/blank group OD value] × 100%,
Then do linear regression with the inhibition of cancer cell rate that the logarithmic value of each concentration of test sample is corresponding to each concentration, obtain docs-effect equation, go out the half-inhibition concentration (IC of each test sample to experiment cancer cells from gained docs-effect Equation for Calculating
50); Each data replicate(determination) five times, asks its mean value, the results are shown in Table shown in 1.
Anti-tumor activity (the IC of each test sample of table 1
50)
As can be seen from Table 1, the inhibit activities of the compound that embodiment 1-9 provides to experiment 5 kinds of cancer cells is significantly better than the activity of parent compound levofloxacin, and especially the activity of majority of compounds is better than the activity of contrast Hydroxycamptothecin.More meaningfully, the compound that embodiment 1-9 provides demonstrates lower 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, then study targetedly, so compound of the present invention has strong anti-tumor activity and lower toxicity, by with the acceptable sour salify of human body or be mixed with antitumor drug with pharmaceutical carrier.
Claims (7)
1. a hand oxazine 3 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative, is characterized in that, has the general structure as shown in the formula (I):
Wherein, R is ethyl or cyclopropyl or fluoro ethyl;
R
1for hydrogen atom or methyl or ethyl;
R
2for hydrogen atom or methyl;
X is N, CH, the carbon atom of halogen substiuted or the carbon atom of methoxy substitution.
2. hand oxazine according to claim 13 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative, is characterized in that, this compound is left-handed photosensitiveness, and the absolute configuration of chiral carbon is S type, is specially the compound of following structure:
3. Shou oxazine according to claim 1 and 23 of quinoline ring, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative, is characterized in that, concrete preparation process comprises:
(1) with the fluoroquinolone carboxylic shown in formula (II) for raw material, obtain 2,3-dihydro fluoroquinolones shown in formula (III) through sodium borohydride reduction decarboxylation,
Wherein, R is ethyl or cyclopropyl or 2-fluoro ethyl,
R
1for hydrogen atom or methyl or ethyl,
R
2for hydrogen atom or methyl,
X is N, CH, the carbon atom of the carbon atom that fluorine replaces or methoxy substitution;
(2) by levofloxacin through sodium borohydride reduction decarboxylation, then by reduction decarboxylate successively through formylation, oxidation make 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, reflux 12 ~ 24 hours under alkaline condition, there is condensation reaction, after reaction terminates, 3 of the Shou oxazine shown in formula (I) quinoline ring can be obtained, 3 '-methylene radical-bis-fluoro quinolone derivative through aftertreatment.
4. Shou oxazine according to claim 33 of quinoline ring, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative, it is characterized in that, the mol ratio of 2,3-dihydro fluoroquinolones shown in described formula (III) and the compound shown in formula (IV) is 1:1.0 ~ 1.2.
5. Shou oxazine according to claim 33 of quinoline ring, the preparation method of 3 '-methylene radical-bis-fluoro quinolone derivative, it is characterized in that, described alkali is at least one in pyridine, triethylamine, piperidines, morpholine, piperazine, potassium hydroxide, sodium hydroxide, calcium hydroxide, salt of wormwood and sodium carbonate.
6., if right is as required Shou oxazine as described in 1 or 2 and 3 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative is preparing the application in antitumor drug.
7. Shou oxazine according to claim 63 of quinoline ring, 3 '-methylene radical-bis-fluoro quinolone derivative, preparing the application in antitumor drug, is characterized in that, described antitumor drug is treatment bladder cancer, cancer of the stomach or pancreatic cancer drug.
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