CN104844619B - A kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application - Google Patents

A kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application Download PDF

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CN104844619B
CN104844619B CN201510143574.9A CN201510143574A CN104844619B CN 104844619 B CN104844619 B CN 104844619B CN 201510143574 A CN201510143574 A CN 201510143574A CN 104844619 B CN104844619 B CN 104844619B
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ofloxacin
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rhodanine
amide derivatives
unsaturated ketone
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CN104844619A (en
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刘彬
王蕊
付建民
闫强
吴书敏
倪礼礼
胡国强
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Jiangsu Shaxing Chemical Co ltd
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Henan University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
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Abstract

The invention discloses a kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application, adopt as shown in the formula I chemical structure of general formula:

Description

A kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application
Technical field
The invention belongs to original new drug synthesis technical field, be specifically related to a kind of Ofloxacin (rhodanine beta-unsaturated ketone) acylAmine derivant, also relate to simultaneously the preparation method of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and preparationApplication in antineoplastic.
Background technology
New drug innovation originates from the discovery of primer, and is to find primer based on structure or machine-processed rational drug designEffective ways. Antibacterial fluoquinolone is taking the fluoro-quinoline of 1-replacement-6-(naphthyridines)-4-ketone-3-carboxylic acid as advantage skeleton, its workWith target spot be topoisomerase (Topo), this enzyme structure in function, have similar to corresponding Topo in mammalian cellProperty, and this enzyme is also the important function target of current antineoplastic. Therefore, the structural modification to existing fluoquinolone medicineIts antibacterial activity can be converted into antitumor activity, be expected to develop new antineoplastic. Existing research is found, fluoquinoloneC-3 carboxyl is not the necessary pharmacophore of antitumor activity, carries another antitumor activity taking C-3 acylamino-as connection chainPharmacophore, can realize the stack of different pharmacophore activity, and has found to have the candidate compound of antitumor activity. Meanwhile, existHave in five yuan of thiazolidine heterocyclic ketone of extensive pharmacologically active, rhodanine has become the advantage medicine that builds new drug molecular chemistry skeletonEffect is rolled into a ball and is widely used. Wherein the modification of rhodanine skeleton is mainly comprised the condensation reaction shape of 5-position active methylene group and aldehydeThe α that becomes C=C key and construct, alpha, beta-unsaturated ketone derivative, or 3-bit amino and carboxylic acids amalgamation formation aminocarboxylic acids or acid amidesDerivatives such as class or for to improve the water-soluble of Rhodanine derivant are introduced multiamide base peptide class on rhodanine skeleton substituting group againSide chain modify, to improve its bioavilability, to promote it to patent medicine sexual development. But, fluoquinolone skeleton and rhodanine boneMolecular structure between frame builds and has not yet to see report.
Summary of the invention
The object of this invention is to provide a kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives, oxygen is provided simultaneouslyThe preparation method and application of Flucloxacillin (rhodanine beta-unsaturated ketone) amide derivatives.
In order to realize above object, the technical solution adopted in the present invention is: (rhodanine is unsaturated for a kind of OfloxacinKetone) amide derivatives, its chemical structural formula is as shown in general formula (I):
Formula (I)
Aromatic substituent Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring. This compounds is specially following structureCompound:
The preparation method of Ofloxacin of the present invention (rhodanine beta-unsaturated ketone) amide derivatives, with shown in formula (II)Ofloxacin is that raw material is prepared from,
Formula (II)
Concrete preparation process is as follows:
1) Ofloxacin shown in formula (II) and hydrazine hydrate are directly carried out to hydrazinolysis and react Ofloxacin shown in the formula of making (III)Hydrazides,
Formula (III)
The detailed operating procedure of preparation formula (III) can reference literature (Hu Guoqiang etc. fluoquinolone C-3 acylhydrazone syntheticAnd antibacterial activity, Chinese Pharmaceutical Journal, 2010,45 (11): 867-870);
2) by compound shown in formula (III) and two-(carboxymethyl) trithiocarbonate back flow reaction 12 hours in water, putPut room temperature, liquid ammonia alkalinization, filters, and collects the solid producing, and by suitable solvent recrystallization, makes the oxygen fluorine sand shown in formula (IV)Star (rhodanine) amide intermediate;
Concrete operation step is: Ofloxacin hydrazides (10.0g, 27.0mmol) and two-(carboxymethyl) trithiocarbonate(7.2g, 32.0mmol) in water (300mL) back flow reaction to raw material disappear (TLC detect, VChloroform：VMethyl alcohol=5:1). Cooling chamberTemperature, alkalizes to pH8.0 with concentrated ammonia liquor, places 12 hours. The solid that filter collection produces, dry. Crude product is recrystallized with absolute ethyl alcohol,Obtain yellow crystal formula (IV), yield 83.7%, mp186-188 DEG C.1HNMR(400MHz,CDCl3):1.43(d,J＝6.8Hz,3H,CH3),2.24(s,3H,N-CH3),2.65-3.37(m,8H,piperazine-H),4.36-4.86(m,3H,OCH2CHN),5.12(s,2H,SCH2),7.65(d,J＝13.2Hz,5-H),8.78(s,1H,2-H),10.68(s,1H,NH)。
3) compound shown in formula (IV) and aromatic aldehyde are carried out to condensation reaction, question response under the catalysis of alkali in glacial acetic acidCompletely through process target compound suc as formula shown in (I).
Formula (I)
As further improvement, Ofloxacin (rhodanine) acid amides shown in formula (IV) and aromatic aldehyde mole be 1:1.0～1.2。
Alkali in described step (4) is at least one in pyridine, triethylamine, piperidines, morpholine, potassium acetate and sodium acetate.
Described a kind of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives prepare in antineoplastic shouldWith.
Described antineoplastic is Hepatoma therapy, cancer of pancreas or leukemia medicament.
The principle of hybridization of a kind of Ofloxacin of the present invention (rhodanine beta-unsaturated ketone) amide derivatives based on pharmacophore,By fluoquinolone, rhodanine, α, the effective combination of the pharmacophores such as alpha, beta-unsaturated ketone and acid amides, design synthesized Ofloxacin (aroundTannin beta-unsaturated ketone) amide derivatives, realize the complementation of different structure pharmacophore and active stack, thereby reached increasingThe effect of effect toxicity reduction, can be used as the antineoplastic exploitation of brand new.
Detailed description of the invention
Below by specific embodiment, technical scheme of the present invention is elaborated.
Prepare compound (I) before, first need to prepare midbody compound (IV), being prepared as follows (IV):
Be prepared from taking the Ofloxacin shown in formula (II) as raw material,
Formula (II)
Concrete preparation process is as follows:
1) Ofloxacin shown in formula (II) and hydrazine hydrate are directly carried out to hydrazinolysis and react Ofloxacin shown in the formula of making (III)Hydrazides,
Formula (III)
The detailed operating procedure of preparation formula (III) can reference literature (Hu Guoqiang etc. fluoquinolone C-3 acylhydrazone syntheticAnd antibacterial activity, Chinese Pharmaceutical Journal, 2010,45 (11): 867-870);
2) by compound shown in formula (III) and two-(carboxymethyl) trithiocarbonate back flow reaction 12 hours in water, putPut room temperature, liquid ammonia alkalinization, filters, and collects the solid producing, and by suitable solvent recrystallization, makes the oxygen fluorine sand shown in formula (IV)Star (rhodanine) amide intermediate;
Formula (IV)
Concrete operation step is: Ofloxacin hydrazides (10.0g, 27.0mmol) and two-(carboxymethyl) trithiocarbonate(7.2g, 32.0mmol) in water (300mL) back flow reaction to raw material disappear (TLC detect, VChloroform：VMethyl alcohol=5:1). Cooling chamberTemperature, alkalizes to pH8.0 with concentrated ammonia liquor, places 12 hours. The solid that filter collection produces, dry. Crude product is recrystallized with absolute ethyl alcohol,Obtain yellow crystal formula (IV), yield 83.7%, mp186-188 DEG C.1HNMR(400MHz,CDCl3):1.43(d,J＝6.8Hz,3H,CH3),2.24(s,3H,N-CH3),2.65-3.37(m,8H,piperazine-H),4.36-4.86(m,3H,OCH2CHN),5.12(s,2H,SCH2),7.65(d,J＝13.2Hz,5-H),8.78(s,1H,2-H),10.68(s,1H,NH)。
Embodiment 1
Ofloxacin (5-benzene methene base-rhodanine-3-yl)-acid amides (I-1), its chemical structural formula is:
Be that Ar in formula I is phenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds benzaldehyde 0.25g (2.4mmol), hybrid reactionThing back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g 60 DEG C of decolourings0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sodium sulfateDry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-1), productive rate72.8％，m.p.193-195℃。1HNMR(400MHz,CDCl3)δ:1.46(d,J＝6.8Hz,3H,CH3),2.25(s,3H,N-CH3),2.68-3.38(m,8H,piperazine-H),4.43-4.87(m,3H,OCH2CHN),7.28-7.76(m,6H,Ph-H and 5-H), 8.32 (s, 1H ,=CH), 8.82 (s, 1H, 2-H), 10.74 (s, 1H, NH); MS (m/z): 580[M+H]+, calculate(C28H26FN5O4S2):579.68。
Embodiment 2
Ofloxacin (5-is to methoxybenzene methene base-rhodanine-3-yl)-acid amides (I-2), its chemical structural formula is:
Be that Ar in formula I is p-methoxyphenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds P-methoxybenzal-dehyde 0.30g (2.2mmol),Mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g 60DEG C decolouring 0.5h, filter. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrousDried over sodium sulfate. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-2), producesRate 81.6%, m.p.196-198 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.24(s,3H,N-CH3),2.73-3.36(m,8H,piperazine-H),3.86(s,3H,OCH3),4.46-4.88(m,3H,OCH2CHN), 7.52 (d, J=7.4Hz, 2H, Ph-H), 7.67-7.78 (m, 3H, Ph-H and 5-H), 8.34 (s, 1H ,=CH),8.84(s,1H,2-H),10.68(s,1H,NH)；MS(m/z):610[M+H]+, calculate (C29H28FN5O5S2):609.70。
Embodiment 3
Ofloxacin (5-O-methoxy benzene methene base-rhodanine-3-yl) acid amides (I-3), its chemical structural formula is:
Be that Ar in formula I is o-methoxyphenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl) acid amides (IV) 1.0g (2.0mmol) and nothingWater sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds o-methoxybenzaldehyde 0.30g (2.2mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-3), productive rate62.4％，m.p.175-177℃。1HNMR(400MHz,CDCl3)δ:1.46(d,J＝6.8Hz,3H,CH3),2.24(s,3H,N-CH3),2.85-3.37(m,8H,piperazine-H),3.88(s,3H,OCH3),4.45-4.87(m,3H,OCH2CHN),7.55-7.84 (m, 5H, Ph-H and 5-H), 8.36 (s, 1H ,=CH), 8.87 (s, 1H, 2-H), 10.75 (s, 1H, NH); MS (m/z):610[M+H]+, calculate (C29H28FN5O5S2):609.70。
Embodiment 4
Ofloxacin [5-(3,4-, bis-Oxymethylenes) benzene methene base-rhodanine-3-yl]-acid amides (I-4), its chemical constitutionFormula is:
Be that Ar in formula I is 3,4-(two Oxymethylenes) phenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 3,4-(two Oxymethylenes) benzaldehyde 0.30g(2.0mmol), mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds 0.1g'sActive carbon, at 60 DEG C of decolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), is associated withMachine phase, anhydrous sodium sulfate drying. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystallizationThing (I-4), productive rate 86.0%, m.p.214-216 DEG C.1HNMR(400MHz,CDCl3)δ:1.45(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.03-3.38(m,8H,piperazine-H),4.46-4.85(m,3H,OCH2CHN),7.68-7.86 (m, 4H, Ph-H and 5-H), 8.38 (s, 1H ,=CH), 8.88 (s, 1H, 2-H), 10.77 (s, 1H, NH); MS (m/z):624[M+H]+, calculate (C29H26FN5O6S2):623.69。
Embodiment 5
Ofloxacin [5-(3,4,5-trimethoxy methyl) benzene methene base-rhodanine-3-yl]-acid amides (I-5), its chemistry knotStructure formula is:
Be that Ar in formula I is 3,4,5-trimethoxy methylene phenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 3,4,5-Trimethoxybenzaldehyde 0.43g(2.2mmol), mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds 0.1g'sActive carbon, at 60 DEG C of decolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), is associated withMachine phase, anhydrous sodium sulfate drying. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystallizationThing (I-5), productive rate 75.6%, m.p.194-196 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),2.76-3.35(m,8H,piperazine-H),4.47-4.86(m,3H,OCH2CHN),7.67(d,J＝13.2Hz,1H,5-H),8.14(s,2H,Ph-H),8.37(s,1H,＝CH)，8.86(s,1H,2-H),10.68(s,1H,NH)；MS(m/z):670[M+H]+, calculate (C31H32FN5O7S2):669.76。
Embodiment 6
Ofloxacin (5-is to methylbenzene methene base-rhodanine-3-yl)-acid amides (I-6), its chemical structural formula is:
Be that Ar in formula I is p-methylphenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds p-tolyl aldehyde 0.29g (2.4mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-6), productive rate63.5％，m.p.172-174℃。1HNMR(400MHz,CDCl3)δ:1.46(d,J＝6.8Hz,3H,CH3),2.26，2.32(2s,6H,Ph-CH3And N-CH3),2.62-3.34(m,8H,piperazine-H),4.46-4.86(m,3H,OCH2CHN),7.48(d,J＝7.2Hz,2H,Ph-H),7.74(d,J＝7.2Hz,2H,Ph-H),7.83(d,J＝13.2Hz,1H,5-H),8.36(s,1H,＝CH)，8.87(s,1H,2-H),10.66(s,1H,NH)；MS(m/z):594[M+H]+, calculate(C29H28FN5O4S2):593.70。
Embodiment 7
Ofloxacin (5-is to chlorobenzene methene base-rhodanine-3-yl)-acid amides (I-7), its chemical structural formula is:
Be that Ar in formula I is rubigan.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 4-chloro-benzaldehyde 0.29g (2.1mmol), mixesReactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g de-at 60 DEG CLook 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous slufuric acidSodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-7), productive rate74.8％，m.p.168-170℃。1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.27(s,3H,N-CH3),3.08-3.41(m,8H,piperazine-H),4.47-4.88(m,3H,OCH2CHN),7.68(d,J＝7.2Hz,2H,Ph-H),7.86(d,J＝13.2Hz,1H,5-H),8.12(d,J＝7.2Hz,2H,Ph-H),8.38(s,1H,＝CH)，8.92(s,1H,2-H),10.75(s,1H,NH)；MS(m/z):614[M+H]+, calculate (C28H25ClFN5O4S2):614.12。
Embodiment 8
Ofloxacin (5-is to fluorobenzene methene base-rhodanine-3-yl)-acid amides (I-8), its chemical structural formula is:
Be Ar in formula I for to fluorophenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 4-Fluorobenzaldehyde 0.30g (2.4mmol), mixesReactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g de-at 60 DEG CLook 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous slufuric acidSodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-8), productive rate81.6％，m.p.206-208℃。1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.31(s,3H,N-CH3),3.06-3.44(m,8H,piperazine-H),4.48-4.88(m,3H,OCH2CHN),7.74(d,J＝7.2Hz,2H,Ph-H),7.88(d,J＝13.2Hz,1H,5-H),8.16(d,J＝7.2Hz,2H,Ph-H),8.41(s,1H,＝CH)，8.96(s,1H,2-H),10.83(s,1H,NH)；MS(m/z):598[M+H]+, calculate (C28H25F2N5O4S2):597.67。
Embodiment 9
Ofloxacin (5-p-nitrophenyl methene base-rhodanine-3-yl)-acid amides (I-9), its chemical structural formula is:
Be that Ar in formula I is p-nitrophenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds paranitrobenzaldehyde 0.30g (2.0mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-9), productive rate82.0％，m.p.223-225℃。1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.34(s,3H,N-CH3),3.07-3.46(m,8H,piperazine-H),4.48-4.91(m,3H,OCH2CHN),7.78(d,J＝7.2Hz,2H,Ph-H),7.89(d,J＝13.2Hz,1H,5-H),8.17(d,J＝7.2Hz,2H,Ph-H),8.43(s,1H,＝CH)，8.97(s,1H,2-H),10.86(s,1H,NH)；MS(m/z):625[M+H]+, calculate (C28H25N6O6S2):624.67。
Embodiment 10
Ofloxacin (5-pyridine-4-methene base-rhodanine-3-yl)-acid amides (I-10), its chemical structural formula is:
Be that Ar in formula I is 4-pyridine radicals.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds to Pyridine-4-Carboxaldehyde 0.24g (2.2mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-10), producesRate 70.3%, m.p.231-233 DEG C.1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.33(s,3H,N-CH3),3.06-3.52(m,8H,piperazine-H),4.51-4.94(m,3H,OCH2CHN),8.05(d,J＝13.2Hz,1H,5-H),8.38(s,1H,＝CH)，8.78(d,J＝6.4Hz,2H,Py-H),8.89(d,J＝6.4Hz,2H,Py-H),9.13(s,1H,2-H),11.26(s,1H,NH)；MS(m/z):581[M+H]+, calculate (C27H25N6O4S2):580.66。
Embodiment 11
Ofloxacin (5-pyridine-3-methene base-rhodanine-3-yl)-acid amides (I-11), its chemical structural formula is:
Be that Ar in formula I is 3-pyridine radicals.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds pyridine-3-formaldehyde 0.24g (2.2mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-11), producesRate 76.5%, m.p.213-215 DEG C.1HNMR(400MHz,CDCl3)δ:1.46(d,J＝6.8Hz,3H,CH3),2.30(s,3H,N-CH3),2.86-3.43(m,8H,piperazine-H),4.47-4.90(m,3H,OCH2CHN),7.88(d,J＝13.2Hz,1H,5-H),8.35(s,1H,＝CH)，8.76-8.87(m,4H,Py-H),9.06(s,1H,2-H),11.16(s,1H,NH)；MS(m/z):581[M+H]+, calculate (C27H25N6O4S2):580.66。
Embodiment 12
Ofloxacin (5-furans-2-methene base-rhodanine-3-yl)-acid amides (I-12), its chemical structural formula is:
Be that Ar in formula I is 2-furyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds furans-2-formaldehyde 0.20g (2.1mmol), mixedClose reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g at 60 DEG CDecolouring 0.5h, filters. Filtrate is alkalized to pH9.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrous sulphurAcid sodium is dry. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-12), producesRate 73.4%, m.p.196-198 DEG C.1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.28(s,3H,N-CH3),2.76-3.41(m,8H,piperazine-H),4.46-4.88(m,3H,OCH2CHN),6.82-7.76(m,3H,furan),7.92(d,J＝13.2Hz,1H,5-H),8.34(s,1H,＝CH)，8.96(s,1H,2-H),11.05(s,1H,NH)；MS(m/z):570[M+H]+, calculate (C26H24N5O5S2):569.64。
Embodiment 13
Ofloxacin (5-is to carboxyl phenyl methene base-rhodanine-3-yl)-acid amides (I-13), its chemical structural formula is:
Be that Ar in formula I is 4-carboxyl phenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 4-carboxyl-benzaldehyde 0.33g (2.2mmol),Mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds the active carbon of 0.1g 60DEG C decolouring 0.5h, filter. Filtrate is alkalized to pH7.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), merges organic phase, anhydrousDried over sodium sulfate. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystal (I-13),Productive rate 72.6%, m.p.235-237 DEG C.1HNMR(400MHz,CDCl3)δ:1.53(d,J＝6.8Hz,3H,CH3),2.35(s,3H,N-CH3),3.14-3.58(m,8H,piperazine-H),4.54-4.97(m,3H,OCH2CHN),7.88(d,J＝7.2Hz,2H,Ph-H),8.20(d,J＝13.2Hz,1H,5-H),8.46(s,1H,＝CH)，9.17(s,1H,2-H),11.31(s,1H,NH)；MS(m/z):624[M+H]+, calculate (C29H26N5O6S2):623.69。
Embodiment 14
Ofloxacin (5-is to sulfoamido benzene methene base-rhodanine-3-yl)-acid amides (I-14), its chemical structural formula is:
Be that Ar in formula I is 4-sulfoamido phenyl.
The preparation method of this compound is: get Ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol) andAnhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, adds 4-sulfoamido-benzaldehyde 0.43g(2.3mmol), mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds 0.1g'sActive carbon, at 60 DEG C of decolouring 0.5h, filters. Filtrate is alkalized to pH7.0 with concentrated ammonia liquor, with chloroform recovery (3 × 15mL), is associated withMachine phase, anhydrous sodium sulfate drying. Decompression and solvent recovery, to dry, with ethanol-DMF (V:V=5:1) recrystallization, obtains faint yellow crystallizationThing (I-14), productive rate 78.2%, m.p.246-248 DEG C.1HNMR(400MHz,CDCl3)δ:1.52(d,J＝6.8Hz,3H,CH3),2.34(s,3H,N-CH3),3.07-3.55(m,8H,piperazine-H),4.52-4.96(m,3H,OCH2CHN),7.73(s,2H,NH2)，8.03(d,J＝7.2Hz,2H,Ph-H),8.17(d,J＝13.2Hz,1H,5-H),8.44(s,1H,＝CH)，8.,62(d,J＝7.2Hz,2H,Ph-H)，9.15(s,1H,2-H),11.38(s,1H,NH)；MS(m/z):659[M+H]+, calculate (C28H27N6O6S3):658.75。
Test example
The extracorporeal anti-tumor of Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives that, embodiment 1-14 provides is livedProperty is measured
1, test sample
Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives providing with embodiment 1-14, and classical antitumorTOPO inhibitor 10-hydroxycamptothecine (HC) and parent compound Ofloxacin (OF) are test sample, totally 16 kinds, wherein HC andOF is control group, and embodiment 1-14 sample is experimental group;
Experiment JEG-3 is respectively that people's liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 are thinThe Shanghai cell bank from the Chinese Academy of Sciences is all bought in born of the same parents' strain. Normal cell adopts VERO African green monkey kidney cell, buys logical in ShanghaiGrowth Science and Technology Ltd..
2, assay method
The concrete steps of assay method are:
(1) first above-mentioned 16 kinds of test samples are used respectively dimethyl sulfoxide (DMSO) (DMSO) to dissolve, be mixed with 1.0 × 10- 2mol·L-1The storing solution of concentration, the RPMI-1640 nutrient solution of the calf serum that is 10% with mass percent concentration afterwards willStoring solution is diluted to has 5 concentration gradients (0.1,1.0,5.0,10.0,50.0 μ molL-1) working solution;
(2) the people's liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and the human leukemia HL60 that take the logarithm growth period are thinBorn of the same parents and VERO cell line, be inoculated in 96 orifice plates with 6000, every hole cell, adds respectively subsequently have 5 of above-mentioned 16 kinds of samplesThe working solution 10 μ L of concentration gradient, and be provided with without medicine control wells (what to add 10 μ L be 10% containing the mass percent concentration of DMSOThe RPMI-1640 nutrient solution of calf serum, and the volume of DMSO be no more than cumulative volume 5%), after 48 hours, every hole adds 5gL–1MTT (tetrazolium bromide) aqueous solution 10 μ L, continue cultivation and add the dodecane that 100 μ L mass percent concentrations are 10% after 4 hoursBase sodium sulphate (SDS) hydroponics 24 hours, then measures OD value at 570nm wavelength place with ELIASA;
(3) inhibiting rate of the test sample of calculating variable concentrations by formula shown in following to cancer cell,
Inhibition of cancer cell rate=[(1-experimental group OD value)/control group OD value] × 100%,
Then with the logarithm value of each concentration of test sample, inhibition of cancer cell rate corresponding to each concentration done to linear regression,To docs-effect equation, calculate the half-inhibition concentration of each test sample to experiment cancer cell from gained docs-effect equation(IC50); Each data parallel determination three times, asks its mean value, the results are shown in Table shown in 1.
Antitumor activity (the IC of the each test sample of table 150)
As can be seen from Table 1, the compound that embodiment 1-14 provides is significantly better than the inhibition activity of testing 3 kinds of cancer cellsThe activity of parent compound Ofloxacin, especially phenyl ring are as assorted in F, nitro, carboxyl, sulfoamido or fragrance with electron-withdrawing groupEncircle as suitable with the activity that contrasts Hydroxycamptothecin in the activity of the compound of pyridine or furans, especially to human pancreas cancer Panc-1 cellAnti-increment activity the strongest, its IC50Value has reached or lower than millimolar concentration. More meaningfully, embodiment 1-14 providesCompound demonstrates lower toxicity to VERO cell, has into the potentiality of the property of medicine. Therefore, according to the general way of drug developmentBe first to carry out conventional antitumor in-vitro screening, then study targetedly according to the program of new drug development. So thisBright compound has strong antitumor activity and lower toxicity, can by with the acceptable sour salify of human body or with medicinal yearBody is mixed with antineoplastic.

Claims (6)

1. Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives, is characterized in that, is specially the change of following structureCompound:
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
。
2. the preparation method of Ofloxacin according to claim 1 (rhodanine beta-unsaturated ketone) amide derivatives, its spyLevy and be, concrete preparation process comprises:
(1) taking the Ofloxacin shown in formula (II) as raw material, make the Ofloxacin hydrazides shown in formula (III) through hydrazinolysis;
Formula (II) formula (III)
(2) compound shown in formula (III) and two-(carboxymethyl) trithiocarbonate are refluxed in water, condensation occurs anti-Should, after reaction finishes, can obtain Ofloxacin (rhodanine) amide derivatives shown in formula (IV) through post processing;
(3) compound shown in formula (IV) and aromatic aldehyde are formed to rhodanine α under the catalysis of alkali, alpha, beta-unsaturated ketone structure, through afterProcessing can obtain the Ofloxacin shown in formula (I) (rhodanine beta-unsaturated ketone) amide derivatives,
Formula (IV) formula (I)
Aromatic rings substituent A r in its Chinese style (I) is、、、、、、、、、、、、Or。
3. the preparation method of Ofloxacin according to claim 2 (rhodanine beta-unsaturated ketone) amide derivatives, its spyLevy and be, the Ofloxacin hydrazides shown in described step (2) Chinese style (III) and two-(carboxymethyl) trithiocarbonate compound, itsMol ratio be 1:1.0 ~ 1.2.
4. the preparation method of Ofloxacin according to claim 2 (rhodanine beta-unsaturated ketone) amide derivatives, its spyLevy and be, Ofloxacin (rhodanine) amide derivatives shown in described step (3) Chinese style (IV) and the mol ratio of aromatic aldehyde are1:1.0 ~ 1.2, described alkali is at least one in pyridine, triethylamine, piperidines, morpholine, potassium acetate and sodium acetate.
5. if right is as required Ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives as described in 1 preparing antineoplasticIn application.
6. Ofloxacin according to claim 5 (rhodanine beta-unsaturated ketone) amide derivatives is being prepared antineoplasticIn application, it is characterized in that, described antineoplastic is Hepatoma therapy, cancer of pancreas or leukemic medicine.
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