CN106317054A - Alpha, beta-nonsaturated ketone derivative of enoxacin, preparation method and application thereof - Google Patents
Alpha, beta-nonsaturated ketone derivative of enoxacin, preparation method and application thereof Download PDFInfo
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- CN106317054A CN106317054A CN201510371788.1A CN201510371788A CN106317054A CN 106317054 A CN106317054 A CN 106317054A CN 201510371788 A CN201510371788 A CN 201510371788A CN 106317054 A CN106317054 A CN 106317054A
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- enoxacin
- beta
- alpha
- unsaturated ketone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- -1 ketone derivative of enoxacin Chemical class 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000002576 ketones Chemical class 0.000 claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- 229960002549 enoxacin Drugs 0.000 claims description 30
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 30
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 26
- 241001597008 Nomeidae Species 0.000 claims description 19
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 150000002240 furans Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 239000004576 sand Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 6
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 4
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 abstract description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 1
- NRCMAYZCPIVABH-UHFFFAOYSA-N Quinacridone Chemical compound N1C2=CC=CC=C2C(=O)C2=C1C=C1C(=O)C3=CC=CC=C3NC1=C2 NRCMAYZCPIVABH-UHFFFAOYSA-N 0.000 abstract 1
- 239000013543 active substance Substances 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 16
- 239000002585 base Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001789 chalcones Chemical class 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000003501 vero cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VWHKEYXRRNSJTN-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carbaldehyde Chemical class C1=CC=C2NC(=O)C(C=O)=CC2=C1 VWHKEYXRRNSJTN-UHFFFAOYSA-N 0.000 description 1
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- XSTQFAUGLCDFRE-VOTSOKGWSA-N CCN(C=C1/C=C/C(c(cc2OC)cc(OC)c2OC)=O)c(nc(c(F)c2)N3CCNCC3)c2C1=O Chemical compound CCN(C=C1/C=C/C(c(cc2OC)cc(OC)c2OC)=O)c(nc(c(F)c2)N3CCNCC3)c2C1=O XSTQFAUGLCDFRE-VOTSOKGWSA-N 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 241000723363 Clerodendrum Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 125000006332 fluoro benzoyl group Chemical group 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an alpha, beta-nonsaturated ketone derivative of enoxacin, a preparation method and an application thereof. According to the invention, a chemical structural general formula is employed as a following formula I, in the formula I, aromatic ring Ar is phenyl ring or substituted phenyl ring or furan ring or pyridine ring. The alpha, beta-nonsaturated ketone derivative of enoxacin realizes effective combination of fluoronaphthalene quinacridone frame and alpha, beta-nonsaturated ketone frame, a novel fluoronaphthalene quinacridone-chalcone compound is constructed, so that the antineoplastic activity of the novel compound is increased, toxic and side effects on the normal cells are reduced, and the derivative can be taken as an antineoplastic active substance for developing the antitumor drugs with a brand new structure.
Description
Technical field
The invention belongs to original new drug synthesis technical field, be specifically related to the α of a kind of enoxacin, alpha, beta-unsaturated ketone derivant, with
Time further relate to the α of a kind of enoxacin, the preparation method of alpha, beta-unsaturated ketone derivant, and its application in antitumor drug.
Background technology
New drug innovation originates from the discovery of primer, and rational drug MOLECULE DESIGN based on structure is to find the effective ways of primer.
In the pharmacophore of various structures, there is α, the chalcone compounds of alpha, beta-unsaturated ketone architectural feature as important natural effectively
Composition, is concerned because having multiple pharmacologically active.But, natural chalcone compounds mostly is the cyclosubstituted α of polyhydroxy benzenes,
Beta-unsaturated ketone compound, because its poor water solublity causes bioavailability relatively low, limits application clinically.It addition,
Also it is the important function target spot of antitumor drug in conjunction with the action target spot topoisomerase of antibacterial flouroquinolone drugs, can be resisted
Bacterium is active Transforming for anti-tumor activity, and find fluoroquinolone C-3 carboxyl be not pharmacophore necessary to anti-tumor activity, can
Replace by bioisostere to improve its anti-tumor activity.Based on this, for improving the water solublity of chalcones, improve it raw
Thing availability and activity, the advantage pharmacophore 1-ethyl-6-fluoro-7-piperazine-1-base of present invention flouroquinolone drugs enoxacin-
Naphthyridines-4 (1H)-one skeleton is as α, the substituent group of alpha, beta-unsaturated ketone structure, and then " class is looked into devise the fluoronaphthalene pyridine of new structure
That ketone " derivant.
To this end, it is an object of the invention to provide the α of a kind of enoxacin, alpha, beta-unsaturated ketone derivant, have antineoplastic action and
Effect, provides the α of a kind of enoxacin, the preparation method of alpha, beta-unsaturated ketone derivant simultaneously.
In order to realize object above, the technical solution adopted in the present invention is: the α of a kind of enoxacin, alpha, beta-unsaturated ketone derivant,
Its chemical structural formula is as shown in formula I:
In formula I, Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring, and this compounds is the compound of following concrete structure:
The α of a kind of enoxacin of the present invention, the preparation method of alpha, beta-unsaturated ketone derivant, is former with the enoxacin shown in formula II
Material is prepared from；
Concrete preparation process is as follows:
1) react to obtain formula III with the enoxacin shown in formula II through sodium borohydride reduction decarboxylation) shown in compound, then with first
Acetoacetic ester condensation reaction prepares the compound shown in formula IV, and last formula IV and activated manganese dioxide aoxidize to obtain the Yi Nuosha shown in formula V
Star aldehyde；
Step 1) Detailed operating procedures be referred to document (Kondo H, Sakamoto F, et al.Studies on prodrugs.7.
Synthesis and antimicrobial activity of 3-formylquinolone derivatives,J.Med.Chem.1988,31,
221～225.) the prodrug research synthesis of .7.3-formoxyl Carbostyril derivative and antimicrobial acivity) method prepare, specifically
Process is as follows:
2) the enoxacin aldehyde shown in formula V is carried out under the catalysis of alkali with the aromatic radical ethyl ketone shown in formula VI in dehydrated alcohol
Aldol reaction, after question response is complete, the treated target compound that obtains is as shown in formula I, and detailed process is as follows:
Wherein, in formula I, Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The general synthetically prepared operating procedure of target compound formula I is: take 1-ethyl-6-fluoro-7-piperazine-1-base-naphthyridines-4 (1H)-one
-3-formaldehyde formula V 1.0g (3.2mmol) is dissolved in 20mL dehydrated alcohol, adds the aromatic radical ethyl ketone (3.2mmol) shown in formula VI
With base catalyst piperidines (0.1mL).Mixed reactant back flow reaction 24h, places room temperature, the solid that filter collection produces, dehydrated alcohol
Recrystallization, obtains pale yellow crystals thing (I).
As further improving, the enoxacin aldehyde shown in formula V with the mol ratio of the aromatic radical ethyl ketone shown in formula VI is
1:1.0～1.2.
Described base catalyst is at least one in piperidines, pyridine, triethylamine, morpholine, potassium acetate and sodium acetate.
The α of described a kind of enoxacin, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant.
Described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemia medicament.
The α of a kind of enoxacin of the present invention, alpha, beta-unsaturated ketone derivant principle of hybridization based on pharmacophore, by fluorine naphthyridones skeleton
With α, alpha, beta-unsaturated ketone pharmacophore is effectively combined, and design has synthesized the α of enoxacin, alpha, beta-unsaturated ketone derivant, it is achieved that
The complementation of different structure pharmacophore and the superposition of activity, thus reached the effect of potentiation toxicity reduction, can swell as the anti-of brand new
Tumor medicine is developed.
Detailed description of the invention
Embodiment 1
1-ethyl-6-fluoro-7-piperazine-1-base-3-(2-benzoyl-ethylene-1-base)-naphthyridines-4 (1H)-one (I-1), its chemical structural formula is:
I.e. Ar in formula I is phenyl.
The preparation method of this compound is: with 1-Phenylethanone. (0.45g, 3.8mmol) substituted VI aromatic radical ethyl ketone, according to above-mentioned
The general preparative methods of object formula I, obtains pale yellow crystals object (I-1), productivity 62.8%, m.p.153～155 DEG C.1H NMR
(400MHz,CD3Cl) δ: 1.62 (3H, t, CH3), 2.76～3.38 (8H, m, piperazine-H), 4.72 (2H, q, N-CH2),
6.73～7.82 (5H, m, Ph-H), 8.12 (1H, d, 5-H), 8.18～8.93 (3H, m, 2-H, 1 '-H and 2 '-H)；MS
(m/z): 407 [M+H]+, calculate (C23H23FN4O2): 406.46.
Embodiment 2
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-methoxybenzoyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-2), its chemistry knot
Structure formula is:
I.e. Ar in formula I is p-methoxyphenyl.
The preparation method of this compound is: with 4-methoxy-acetophenone (0.48g, 3.2mmol) substituted VI aromatic radical ethyl ketone, depend on
According to the general preparative methods of above-mentioned object formula I, obtain pale yellow crystals object (I-2), productivity 65.3%, m.p.155～157 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.65 (3H, t, CH3), 2.86～3.41 (8H, m, piperazine-H), 3.89 (3H, s,
OCH3), 4.74 (2H, q, N-CH2), 7.63～7.88 (4H, m, Ph-H), 8.16 (1H, d, 5-H), 8.31～9.06 (3H,
M, 2-H, 1 '-H and 2 '-H)；MS (m/z): 437 [M+H]+, calculate (C24H25FN4O3): 436.49.
Embodiment 3
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(3,4-dioxymethylene-benzoyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-3),
Its chemical structural formula is:
I.e. Ar in formula I is 3,4-(dioxymethylene) phenyl.
The preparation method of this compound is: with 3,4-dioxymethylene-1-Phenylethanone. (0.52g, 3.2mmol) substituted VI aromatic radical
Ethyl ketone, according to the general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object thing (I-3), productivity 65.5%,
M.p.172～174 DEG C.1.66 (3H, t, CH3), 3.07～3.52 (8H, m, piperazine-H), 4.76 (2H, q, N-CH2), 6.23
(2H, s, OCH2O), 7.66～8.06 (3H, m, Ph-H), 8.18 (1H, d, 5-H), 8.36～9.10 (3H, m, 2-H,
1 '-H and 2 '-H)；MS (m/z): 451 [M+H]+, calculate (C24H23FN4O4): 450.47.
Embodiment 4
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(3,4,5-trimethoxy methyl-benzoyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-4),
Its chemical structural formula is:
I.e. Ar in formula I is 3,4,5-2,4,5-trimethoxyphenyls.
The preparation method of this compound is: with 3,4,5-trimethoxies-1-Phenylethanone. (0.67g, 3.2mmol) substituted VI aromatic radical
Ethyl ketone, according to the general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object thing (I-4), productivity 61.4%,
M.p.153～155 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.64 (3H, t, CH3), 3.12～3.55 (8H, m, piperazines
-H), 3.87,3.92 (9H, 2s, 3 × OCH3), 4.78 (2H, q, N-CH2), 7.84 (2H, s, Ph-H), 8.17 (1H,
D, 5-H), 8.35～9.12 (3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 497 [M+H]+, calculate (C26H29FN4O5):
496.54。
Embodiment 5
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-methyl-benzoyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-5), its chemical constitution
Formula is:
I.e. Ar in formula I is to methylphenyl.
The preparation method of this compound is: with 4-methyl-acetophenone (0.51g, 3.8mmol) substituted VI aromatic radical ethyl ketone, according to
The general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object thing (I-5), productivity 51.6%, m.p.134～136 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.57 (3H, t, CH3), 2.31 (3H, s, Ph-CH3), 2.68～3.37 (8H, m,
Piperazine-H), 4.74 (2H, q, N-CH2), 7.56～7.82 (4H, m, Ph-H), 8.05 (1H, d, 5-H), 8.24～9.03 (3H,
M, 2-H, 1 '-H and 2 '-H)；MS (m/z): 421 [M+H]+, calculate (C24H25FN4O2): 420.49.
Embodiment 6
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(the fluoro-benzoyl of 4-)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-6), its chemical structural formula
For:
I.e. Ar in formula I is to fluoro-phenyl.
The preparation method of this compound is: with 4-fluoro-1-Phenylethanone. (0.44g, 3.2mmol) substituted VI aromatic radical ethyl ketone, according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-6), productivity 64.5%, m.p.161～163 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.71 (3H, t, CH3), 3.12～3.56 (8H, m, piperazine-H), 4.76 (2H, q,
N-CH2), 7.74～8.05 (4H, m, Ph-H), 8.17 (1H, d, 5-H), 8.34～9.15 (3H, m, 2-H, 1 '-H and 2 '-H)；
MS (m/z): 425 [M+H]+, calculate (C23H22F2N4O2): 425.45.
Embodiment 7
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-nitro-benzoyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-7), its chemical constitution
Formula is:
I.e. Ar in formula I is to nitro-phenyl.
The preparation method of this compound is: with 4-nitro-acetophenone (0.53g, 3.2mmol) substituted VI aromatic radical ethyl ketone, according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-7), productivity 66.7%, m.p.171～173 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.73 (3H, t, CH3), 3.16～3.57 (8H, m, piperazine-H), 4.78 (2H, q,
N-CH2), 7.84～8.07 (4H, m, Ph-H), 8.22 (1H, d, 5-H), 8.36～9.18 (3H, m, 2-H, 1 '-H and 2 '-H)；
MS (m/z): 452 [M+H]+, calculate (C23H22FN5O4): 451.46.
Embodiment 8
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-Hydroxy-benzoyIcarbamo)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-8), its chemical structural formula is:
I.e. Ar in formula I is 4-hydroxy-pheny.
The preparation method of this compound is: with 4-hydroxy-acetophenone (0.45g, 3.3mmol) substituted VI aromatic radical ethyl ketone, according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-8), productivity 47.6%, m.p.153～155 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.68 (3H, t, CH3), 3.05～3.51 (8H, m, piperazine-H), 4.74 (2H, q,
N-CH2), 7.72～7.94 (4H, m, Ph-H), 8.13 (1H, d, 5-H), 8.30～9.12 (3H, m, 2-H, 1 '-H and 2 '-H),
10.53 (1H, brs, OH)；MS (m/z): 423 [M+H]+, calculate (C23H23FN4O3): 422.46.
Embodiment 9
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-pyridine-formoxyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-9), its chemical constitution
Formula is:
I.e. Ar in formula I is 4-pyridine radicals.
The preparation method of this compound is: with 4-pyridine-ethyl ketone (0.39g, 3.2mmol) substituted VI aromatic radical ethyl ketone, according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-9), productivity 51.6%, m.p.178～180 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.75 (3H, t, CH3), 3.23～3.63 (8H, m, piperazine-H), 4.82 (2H, q,
N-CH2), 8.23 (1H, d, 5-H), 8.42～9.21 (7H, m, 2-H, 1 '-H, 2 '-H and Py-H)；MS (m/z): 408
[M+H]+, calculate (C22H22FN5O2): 407.45.
Embodiment 10
1-ethyl-6-fluoro-7-piperazine-1-base-3-[2-(4-furan-formyl)-ethylene-1-base]-naphthyridines-4 (1H)-one (I-10), its chemical constitution
Formula is:
I.e. Ar in formula I is 2-furyl.
The preparation method of this compound is: with 2-furan-ethyl ketone (0.42g, 3.8mmol) substituted VI aromatic radical ethyl ketone, according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-10), productivity 57.6%, m.p.163～165 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.68 (3H, t, CH3), 3.14～3.58 (8H, m, piperazine-H), 4.76 (2H, q,
N-CH2), 6.87～7.78 (3H, m, furan-H), 8.15 (1H, d, 5-H), 8.37～9.18 (3H, m, 2-H and 1 '-H,
2’-H)；MS (m/z): 397 [M+H]+, calculate (C21H21FN4O3): 396.42.
Test example
One, the α of a kind of enoxacin that embodiment 1-10 provides, the anti tumor activity in vitro of alpha, beta-unsaturated ketone derivant measures
1, test sample
With the α of a kind of enoxacin that embodiment 1-10 provides, alpha, beta-unsaturated ketone derivant and classical antitumor TOPO inhibitor
10-hydroxycamptothecine (HC) and parent compound enoxacin (EN) are test sample, and totally 12 kinds, wherein HC and PF is
Matched group, embodiment 1-10 sample is experimental group；
Experiment JEG-3 is people's hepatocarcinoma Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 cell respectively
Strain is all bought from Chinese Academy of Sciences's Shanghai cell bank.Normal cell uses VERO African green monkey kidney cell, buys and sends in upper Cacumen et folium clerodendri mandarinori (Clerodendron mandarinorum Diels)
Bio tech ltd.
2, assay method
Concretely comprising the following steps of assay method:
1) first above-mentioned 12 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) respectively, be configured to 1.0 × 10-2mol·L-1
The storing solution of concentration, dilutes storing solution with the RPMI-1640 culture fluid of the calf serum that mass percent concentration is 10% afterwards
Become there are 5 Concentraton gradient (0.1,1.0,5.0,10.0,50.0 μm ol L-1) working solution；
2) take the logarithm people's hepatocarcinoma Hep-3B cell of trophophase, human pancreas cancer Panc-1 cell and human leukemia HL60 cell and
VERO cell strain, is inoculated in 96 orifice plates with 6000, every hole cell, and be separately added into above-mentioned 12 kinds of samples subsequently has 5
The working solution of Concentraton gradient, after 48 hours, every hole adds 5g L–1MTT (tetrazolium bromide) solution 10 μ L, continues to be further cultured for 4 hours
Add sodium lauryl sulphate (SDS) solution that 100 μ L mass percent concentrations are 10% afterwards.Cultivate 24 hours, then
At 570nm wavelength, absorbance (OD) value is measured by microplate reader；
3) test sample of the variable concentrations suppression ratio to cancerous cell is calculated by following shown formula,
Inhibition of cancer cell rate=[(1-experimental group OD value)/matched group OD value] × 100%；
Then with the logarithm value of each concentration of test sample, the inhibition of cancer cell rate that each concentration is corresponding is made linear regression, obtain docs-effect
Equation, goes out the test sample half-inhibition concentration (IC to experiment cancerous cell from gained docs-effect Equation for Calculating50)；Each data
Parallel assay three times, seeks its meansigma methods, the results are shown in Table shown in 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 the compound that embodiment 1-10 provides is significantly stronger than parent to the inhibitory activity of 3 kinds of cancerous cell of experiment
The activity of compound enoxacin (EN), especially part of compounds are thin to people's hepatocarcinoma Hep-3B cell and human pancreas cancer Panc-1
Born of the same parents, the especially growth inhibitory activity to human pancreas cancer Panc-1 cell are better than the activity of comparison hydroxycamptothecin, its IC50Value reaches
Arrive or less than micro-molar concentration.More meaningful, VERO cell is demonstrated relatively low by the compound that embodiment 1-10 provides
Toxicity, 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,
Study the most targetedly, so the compound of the present invention has strong anti-tumor activity and relatively low toxicity, can by with
The acceptable acid of human body becomes salt or is mixed with antitumor drug with pharmaceutical carrier.
Claims (6)
1. a α for enoxacin, alpha, beta-unsaturated ketone derivant, it is characterised in that there is the general structure of following formula I:
Wherein, in formula I, aromatic rings Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of enoxacin the most according to claim 1, alpha, beta-unsaturated ketone analog derivative, it is typically characterized by with following
The typical compound of structure:
The α of a kind of enoxacin the most according to claim 1 and 2, the preparation method of alpha, beta-unsaturated ketone derivant, its feature exists
In, concrete preparation process includes:
1) with the enoxacin shown in formula II as raw material, the compound shown in formula III is prepared through the reaction of sodium borohydride reduction decarboxylation,
Then the compound shown in formula IV is prepared with Ethyl formate condensation reaction；Last formula IV prepares with activated manganese dioxide oxidation reaction and depends on
Promise sand star aldehyde formula V:
2) enoxacin aldehyde shown in formula V and aromatic radical ethyl ketone are formed under the catalysis of alkali α, alpha, beta-unsaturated ketone structure, through after place
Reason can obtain the α of a kind of enoxacin shown in formula I, alpha, beta-unsaturated ketone derivant:
Wherein, the aromatic radical Ar in formula I is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of enoxacin the most according to claim 3, the preparation method of alpha, beta-unsaturated ketone derivant, it is characterised in that
Enoxacin aldehyde shown in described formula V is 1:1.0～1.2 with the mol ratio of aromatic radical ethyl ketone.
5. as right is required the α of a kind of enoxacin as described in 1 or 2, and alpha, beta-unsaturated ketone derivant is in preparing antitumor drug
Application.
The α of a kind of enoxacin the most according to claim 5, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant,
It is characterized in that, described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemic medicine.
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| CN104557973A (en) * | 2014-12-23 | 2015-04-29 | 河南大学 | 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative |
| CN104628702A (en) * | 2015-01-29 | 2015-05-20 | 河南大学 | Cyclopropylfluoroquinolone C-3 s-triazole thioether ketone thiosemicarbazone compound and preparation method and application thereof |
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| CN104557973A (en) * | 2014-12-23 | 2015-04-29 | 河南大学 | 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative |
| CN104628702A (en) * | 2015-01-29 | 2015-05-20 | 河南大学 | Cyclopropylfluoroquinolone C-3 s-triazole thioether ketone thiosemicarbazone compound and preparation method and application thereof |
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