CN104844618B - A kind of lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application - Google Patents
A kind of lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of lavo-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
Technical field
The invention belongs to original new drug synthesis technical field, be specifically related to a kind of lavo-ofloxacin (rhodanine beta-unsaturated ketone)Amide derivatives, also relate to simultaneously a kind of lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives preparation method andIts application 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 lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives, provide simultaneouslyThe preparation method of this compounds and in the application of preparing in antineoplastic.
In order to realize above object, the technical solution adopted in the present invention is: (rhodanine is unsaturated for a kind of lavo-ofloxacinKetone) amide derivatives, its chemical structure of general formula is suc as formula shown in (I):
Formula (I)
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring. This compounds is specially the compound of following structure:
The preparation method of lavo-ofloxacin of the present invention (rhodanine beta-unsaturated ketone) amide derivatives, shown in formula (II)Lavo-ofloxacin be that raw material is prepared from,
Formula (II)
Concrete preparation process is as follows:
1) lavo-ofloxacin shown in formula (II) and hydrazine hydrate are directly carried out to hydrazinolysis and react left oxygen fluorine shown in the formula of making (III)Husky star 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,Place room temperature, liquid ammonia alkalinization, filters, and collects the solid producing, and by suitable solvent recrystallization, makes the left oxygen shown in formula (IV)Flucloxacillin (rhodanine) amide intermediate;
Formula (IV)
Concrete operation step is: lavo-ofloxacin hydrazides (10.0g, 27.0mmol) and two-(carboxymethyl) trithiocarbonic acidEster (7.2g, 32.0mmol) disappears at water (300mL) back flow reaction to raw material, and (TLC detects, VChloroform：VMethyl alcohol=5:1). Cooling chamberTemperature, alkalizes to pH8.0 with concentrated ammonia liquor, places 12h. The solid that filter collection produces, dry. Crude product is recrystallized with absolute ethyl alcohol, obtains yellowLook crystallization formula (IV), yield 76.6%, mp181-183 DEG C.1HNMR(400MHz,CDCl3):1.45(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.05-3.48(m,8H,piperazine-H),4.42-4.87(m,3H,OCH2CHN),5.14(s,2H,SCH2),7.68(d,J＝13.2Hz,5-H),8.77(s,1H,2-H),10.66(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, (rhodanine) acid amides of the lavo-ofloxacin 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 lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives is in the application of preparing in antineoplastic.
Described antineoplastic is Hepatoma therapy, cancer of pancreas or leukemia medicament.
A kind of lavo-ofloxacin of the present invention (rhodanine beta-unsaturated ketone) amalgamation of amide derivatives based on pharmacophore is formerReason, by chirality fluoquinolone, rhodanine, α, the effective combination of the pharmacophores such as alpha, beta-unsaturated ketone and acid amides, left oxygen has been synthesized in designFlucloxacillin (rhodanine beta-unsaturated ketone) amide derivatives, has realized the complementation of different structure pharmacophore and active stack, fromAnd reached the effect of synergy 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):
1) lavo-ofloxacin shown in formula (II) and hydrazine hydrate are directly carried out to hydrazinolysis and react left oxygen fluorine shown in the formula of making (III)Husky star hydrazides;
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,Place room temperature, liquid ammonia alkalinization, filters, and collects the solid producing, and by suitable solvent recrystallization, makes the left oxygen shown in formula (IV)Flucloxacillin (rhodanine) amide intermediate;
Formula (IV)
Concrete operation step is: lavo-ofloxacin hydrazides (10.0g, 27.0mmol) and two-(carboxymethyl) trithiocarbonic acidEster (7.2g, 32.0mmol) disappears at water (300mL) back flow reaction to raw material, and (TLC detects, VChloroform：VMethyl alcohol=5:1). Cooling chamberTemperature, alkalizes to pH8.0 with concentrated ammonia liquor, places 12h. The solid that filter collection produces, dry. Crude product is recrystallized with absolute ethyl alcohol, obtains yellowLook crystallization formula (IV), yield 76.6%, mp181-183 DEG C.1HNMR(400MHz,CDCl3):1.45(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.05-3.48(m,8H,piperazine-H),4.42-4.87(m,3H,OCH2CHN),5.14(s,2H,SCH2),7.68(d,J＝13.2Hz,5-H),8.77(s,1H,2-H),10.66(s,1H,NH)。
Embodiment 1
Lavo-ofloxacin (2-sulfo--5-benzene methene base-thiazolidin-4-one-3-yl)-acid amides (I-1), its chemical structural formulaFor:
Be that Ar in formula I is phenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add benzaldehyde 0.25g (2.4mmol), mix anti-Answer thing 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 rate67.5％，m.p.185-187℃。1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.07-3.46(m,8H,piperazine-H),4.45-4.88(m,3H,OCH2CHN),7.32-7.78(m,6H,Ph-H and 5-H), 8.33 (s, 1H ,=CH), 8.86 (s, 1H, 2-H), 10.73 (s, 1H, NH); MS (m/z): 580[M+H]+, calculate(C28H26FN5O4S2):579.68。
Embodiment 2
Lavo-ofloxacin (2-sulfo--5-is to methoxybenzene methene base-thiazolidin-4-one-3-yl)-acid amides (I-2), its changeStructural formula is:
Be that Ar in formula I is p-methoxyphenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add P-methoxybenzal-dehyde 0.30g(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-2), productive rate 75.8%, m.p.188-190 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.13-3.47(m,8H,piperazine-H),3.88(s,3H,OCH3),4.46-4.51(m,3H,OCH2CHN), 7.58 (d, J=7.4Hz, 2H, Ph-H), 7.72-7.84 (m, 3H, Ph-H and 5-H), 8.35 (s, 1H,＝CH)，8.89(s,1H,2-H),10.75(s,1H,NH)；MS(m/z):610[M+H]+, calculate (C29H28FN5O5S2):609.70。
Embodiment 3
Lavo-ofloxacin (2-sulfo--5-O-methoxy benzene methene base-thiazolidin-4-one-3-yl) acid amides (I-3), its changeStructural formula is:
Be that Ar in formula I is o-methoxyphenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add o-methoxybenzaldehyde 0.30g(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-3), productive rate 57.4%, m.p.168-170 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.28(s,3H,N-CH3),3.05-3.46(m,8H,piperazine-H),3.87(s,3H,OCH3),4.45-4.89(m,3H,OCH2CHN), 7.68-7.86 (m, 5H, Ph-H and 5-H), 8.36 (s, 1H ,=CH), 8.92 (s, 1H, 2-H), 10.78(s,1H,NH)；MS(m/z):610[M+H]+, calculate (C29H28FN5O5S2):609.70。
Embodiment 4
Lavo-ofloxacin [2-sulfo--5-(3,4-, bis-Oxymethylenes) benzene methene base-thiazolidin-4-one-3-yl]-acid amides(I-4), its chemical structural formula is:
Be that Ar in formula I is 3,4-(two Oxymethylenes) phenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 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 82.5%, m.p.205-207 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),3.05-3.44(m,8H,piperazine-H),4.46-4.87(m,3H,OCH2CHN),7.68-7.85 (m, 4H, Ph-H and 5-H), 8.37 (s, 1H ,=CH), 8.92 (s, 1H, 2-H), 10.76 (s, 1H, NH); MS (m/z):624[M+H]+, calculate (C29H26FN5O6S2):623.69。
Embodiment 5
Lavo-ofloxacin [2-sulfo--5-(3,4,5-trimethoxy methyl) benzene methene base-thiazolidin-4-one-3-yl]-acid amides(I-5), its chemical structural formula is:
Be that Ar in formula I is 3,4,5-trimethoxy methylene phenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 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 68.3%, m.p.182-184 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.26(s,3H,N-CH3),2.86-3.44(m,8H,piperazine-H),4.47-4.87(m,3H,OCH2CHN),7.68(d,J＝13.2Hz,1H,5-H),8.14(s,2H,Ph-H),8.37(s,1H,＝CH)，8.87(s,1H,2-H),10.74(s,1H,NH)；MS(m/z):670[M+H]+, calculate (C31H32FN5O7S2):669.76。
Embodiment 6
Lavo-ofloxacin (2-sulfo--5-is to methylbenzene methene base-thiazolidin-4-one-3-yl)-acid amides (I-6), its chemistryStructural formula is:
Be that Ar in formula I is p-methylphenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add p-tolyl aldehyde 0.29g (2.4mmol),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-6), producesRate 53.6%, m.p.166-168 DEG C.1HNMR(400MHz,CDCl3)δ:1.46(d,J＝6.8Hz,3H,CH3),2.24，2.28(2s,6H,Ph-CH3And N-CH3),2.74-3.38(m,8H,piperazine-H),4.46-4.87(m,3H,OCH2CHN),7.62(d,J＝7.2Hz,2H,Ph-H),7.75(d,J＝7.2Hz,2H,Ph-H),7.82(d,J＝13.2Hz,1H,5-H),8.36(s,1H,＝CH)，8.87(s,1H,2-H),10.68(s,1H,NH)；MS(m/z):594[M+H]+, calculate(C29H28FN5O4S2):593.70。
Embodiment 7
Lavo-ofloxacin (2-sulfo--5-is to chlorobenzene methene base-thiazolidin-4-one-3-yl)-acid amides (I-7), its chemistry knotStructure formula is:
Be that Ar in formula I is rubigan.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 4-chloro-benzaldehyde 0.29g (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-7), productive rate74.8％，m.p.162-164℃。1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.31(s,3H,N-CH3),3.07-3.41(m,8H,piperazine-H),4.47-4.88(m,3H,OCH2CHN),7.67(d,J＝7.2Hz,2H,Ph-H),7.85(d,J＝13.2Hz,1H,5-H),8.16(d,J＝7.2Hz,2H,Ph-H),8.38(s,1H,＝CH)，8.94(s,1H,2-H),10.76(s,1H,NH)；MS(m/z):614[M+H]+, calculate (C28H25ClFN5O4S2):614.12。
Embodiment 8
Lavo-ofloxacin (2-sulfo--5-is to fluorobenzene methene base-thiazolidin-4-one-3-yl)-acid amides (I-8), its chemistry knotStructure formula is:
Be Ar in formula I for to fluorophenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 4-Fluorobenzaldehyde 0.30g (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-8), productive rate73.2％，m.p.197-199℃。1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.33(s,3H,N-CH3),3.07-3.46(m,8H,piperazine-H),4.53-4.88(m,3H,OCH2CHN),7.78(d,J＝7.2Hz,2H,Ph-H),7.88(d,J＝13.2Hz,1H,5-H),8.22(d,J＝7.2Hz,2H,Ph-H),8.44(s,1H,＝CH)，8.97(s,1H,2-H),10.84(s,1H,NH)；MS(m/z):598[M+H]+, calculate (C28H25F2N5O4S2):597.67。
Embodiment 9
Lavo-ofloxacin (2-sulfo--5-p-nitrophenyl methene base-thiazolidin-4-one-3-yl)-acid amides (I-9), its chemistryStructural formula is:
Be that Ar in formula I is p-nitrophenyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add paranitrobenzaldehyde 0.30g (2.0mmol),Mixed reactant back flow reaction 12h. Remove solvent under reduced pressure, residue water (20mL) dissolves, and adds 0.1 active carbon 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 rate76.6％，m.p.213-215℃。1HNMR(400MHz,CDCl3)δ:1.51(d,J＝6.8Hz,3H,CH3),2.35(s,3H,N-CH3),3.11-3.48(m,8H,piperazine-H),4.48-4.93(m,3H,OCH2CHN),7.82(d,J＝7.2Hz,2H,Ph-H),7.93(d,J＝13.2Hz,1H,5-H),8.18(d,J＝7.2Hz,2H,Ph-H),8.46(s,1H,＝CH)，9.11(s,1H,2-H),10.87(s,1H,NH)；MS(m/z):625[M+H]+, calculate (C28H25N6O6S2):624.67。
Embodiment 10
Lavo-ofloxacin (2-sulfo--5-pyridine-4-methene base-thiazolidin-4-one-3-yl)-acid amides (I-10), its chemistryStructural formula is:
Be that Ar in formula I is 4-pyridine radicals.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add to Pyridine-4-Carboxaldehyde 0.24g (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-10),Productive rate 62.8%, m.p.216-218 DEG C.1HNMR(400MHz,CDCl3)δ:1.53(d,J＝6.8Hz,3H,CH3),2.36(s,3H,N-CH3),3.12-3.53(m,8H,piperazine-H),4.52-4.96(m,3H,OCH2CHN),8.11(d,J＝13.2Hz,1H,5-H),8.38(s,1H,＝CH)，8.82(d,J＝6.4Hz,2H,Py-H),8.89(d,J＝6.4Hz,2H,Py-H),9.15(s,1H,2-H),11.25(s,1H,NH)；MS(m/z):581[M+H]+, calculate (C27H25N6O4S2):580.66。
Embodiment 11
Lavo-ofloxacin (2-sulfo--5-pyridine-3-methene base-thiazolidin-4-one-3-yl)-acid amides (I-11), its chemistryStructural formula is:
Be that Ar in formula I is 3-pyridine radicals.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add pyridine-3-formaldehyde 0.24g (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-11),Productive rate 70.6%, m.p.201-203 DEG C.1HNMR(400MHz,CDCl3)δ:1.48(d,J＝6.8Hz,3H,CH3),2.32(s,3H,N-CH3),3.14-3.46(m,8H,piperazine-H),4.48-4.90(m,3H,OCH2CHN),7.88(d,J＝13.2Hz,1H,5-H),8.36(s,1H,＝CH)，8.78-8.88(m,4H,Py-H),9.08(s,1H,2-H),11.15(s,1H,NH)；MS(m/z):581[M+H]+, calculate (C27H25N6O4S2):580.66。
Embodiment 12
Lavo-ofloxacin (2-sulfo--5-furans-2-methene base-thiazolidin-4-one-3-yl)-acid amides (I-12), its chemistryStructural formula is:
Be that Ar in formula I is 2-furyl.
The preparation method of this compound is: get lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add furans-2-formaldehyde 0.20g (2.1mmol),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-12),Productive rate 65.7%, m.p.182-184 DEG C.1HNMR(400MHz,CDCl3)δ:1.47(d,J＝6.8Hz,3H,CH3),2.30(s,3H,N-CH3),2.96-3.43(m,8H,piperazine-H),4.47-4.53(m,3H,OCH2CHN),6.86-7.78(m,3H,furan),7.95(d,J＝13.2Hz,1H,5-H),8.35(s,1H,＝CH)，8.97(s,1H,2-H),11.21(s,1H,NH)；MS(m/z):570[M+H]+, calculate (C26H24N5O5S2):569.64。
Embodiment 13
Lavo-ofloxacin (2-sulfo--5-is to carboxyl phenyl-2-methene base-thiazolidin-4-one-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 lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 4-carboxyl-benzaldehyde 0.33g(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 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-13), productive rate 65.7%, m.p.210-212 DEG C.1HNMR(400MHz,CDCl3)δ:1.55(d,J＝6.8Hz,3H,CH3),2.34(s,3H,N-CH3),3.16-3.58(m,8H,piperazine-H),4.56-5.12(m,3H,OCH2CHN),8.03(d,J＝7.2Hz,2H,Ph-H),8.24(d,J＝13.2Hz,1H,5-H),8.47(s,1H,＝CH)，9.18(s,1H,2-H),11.36(s,1H,NH)；MS(m/z):624[M+H]+, calculate (C29H26N5O6S2):623.69。
Embodiment 14
Lavo-ofloxacin (2-sulfo--5-is to sulfoamido phenyl-2-methene base-thiazolidin-4-one-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 lavo-ofloxacin (rhodanine-3-yl)-acid amides (IV) 1.0g (2.0mmol)Be dissolved in 15mL glacial acetic acid with anhydrous sodium acetate 0.20g (2.4mmol), add 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 64.5%, m.p.222-224 DEG C.1HNMR(400MHz,CDCl3)δ:1.53(d,J＝6.8Hz,3H,CH3),2.37(s,3H,N-CH3),3.15-3.57(m,8H,piperazine-H),4.55-5.13(m,3H,OCH2CHN),7.76(s,2H,NH2)，8.03(d,J＝7.2Hz,2H,Ph-H),8.18(d,J＝13.2Hz,1H,5-H),8.45(s,1H,＝CH)，8.66(d,J＝7.2Hz,2H,Ph-H)，9.17(s,1H,2-H),11.43(s,1H,NH)；MS(m/z):659[M+H]+,Calculate (C28H27N6O6S3):658.75。
Test example
The extracorporeal anti-tumor of lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives that, embodiment 1-14 providesDetermination of activity
1, test sample
Lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives providing with embodiment 1-14, and classical antitumorTOPO inhibitor 10-hydroxycamptothecine (HC) and parent compound lavo-ofloxacin (LOF) they are test sample, totally 16 kinds, whereinHC and LOF are 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 lavo-ofloxacin, especially phenyl ring with electron-withdrawing group as F, nitro, carboxyl, sulfoamido or fragranceHeterocycle is as suitable with the activity that contrasts Hydroxycamptothecin in the activity of the compound of pyridine or furans, especially thin to human pancreas cancer Panc-1Born of the same parents' anti-increment activity is the strongest, its IC50Value has reached or lower than millimolar concentration. More meaningfully, embodiment 1-14 providesCompound VERO cell is demonstrated to lower toxicity, there are into the potentiality of the property of medicine. Therefore, according to the general way of drug developmentFootpath is first to carry out conventional antitumor in-vitro screening, then studies targetedly according to the program of new drug development. So thisThe compound of invention has strong antitumor activity and lower toxicity, can be by with the acceptable sour salify of human body or with medicinalCarrier is mixed with antineoplastic.
Claims (6)
1. lavo-ofloxacin (rhodanine beta-unsaturated ketone) amide derivatives, is characterized in that, is specially following structureCompound:
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
。
2. the preparation method of lavo-ofloxacin according to claim 1 (rhodanine beta-unsaturated ketone) amide derivatives, itsBe characterised in that, concrete preparation process comprises:
(1) taking the lavo-ofloxacin shown in formula (II) as raw material, make the lavo-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 lavo-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 lavo-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 lavo-ofloxacin according to claim 2 (rhodanine beta-unsaturated ketone) amide derivatives, itsBe characterised in that the lavo-ofloxacin hydrazides shown in described formula step (2) Chinese style (III) and two-(carboxymethyl) trithiocarbonateMol ratio be 1:1.0 ~ 1.2.
4. the preparation method of lavo-ofloxacin according to claim 2 (rhodanine beta-unsaturated ketone) amide derivatives, itsBe characterised in that, lavo-ofloxacin (rhodanine) amide derivatives shown in described step (3) Chinese style (IV) and aromatic aldehyde moleThan being 1:1.0 ~ 1.2, described alkali is at least one in pyridine, triethylamine, piperidines, morpholine, potassium acetate and sodium acetate.
5. lavo-ofloxacin according to claim 1 (rhodanine beta-unsaturated ketone) amide derivatives is being prepared antineoplasticApplication in thing.
6. lavo-ofloxacin according to claim 5 (rhodanine beta-unsaturated ketone) amide derivatives is being prepared antineoplasticApplication in thing, is characterized in that, described antineoplastic is Hepatoma therapy, cancer of pancreas or leukemic medicine.
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